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Transcript of Cochrane Alendronate, Risendronate Systematic Review
Alendronate for the primary and secondary prevention of
osteoporotic fractures in postmenopausal women (Review)
Wells GA, Cranney A, Peterson J, Boucher M, Shea B, Welch V, Coyle D, Tugwell P
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library2011, Issue 9
http://www.thecochranelibrary.com
Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
INTERNAL U
SE ONLY
T A B L E O F C O N T E N T S
1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Figure 5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Figure 6. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
13RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 7. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Figure 8. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Figure 9. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Figure 10. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Figure 11. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
Figure 12. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
Figure 13. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
Figure 14. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
Figure 15. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Figure 16. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
Figure 17. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
Figure 18. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
Figure 19. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
Figure 20. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
Figure 21. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
Figure 22. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
31DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 23. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
35AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
35ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
35REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
42CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
57DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
59ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
68FEEDBACK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
72WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
72HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
72CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
72DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
73SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
73INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
iAlendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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[Intervention Review]
Alendronate for the primary and secondary prevention ofosteoporotic fractures in postmenopausal women
George A Wells1, Ann Cranney2, Joan Peterson3, Michel Boucher4, Beverley Shea5, Vivian Welch6, Doug Coyle7, Peter Tugwell8
1Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, Canada. 2Division of Rheumatology, Ottawa
Hospital, Ottawa, Canada. 3Clinical Epidemiology Unit, Ottawa Civic Hospital / Loeb Research Institute, Ottawa, Canada. 4HTA
Development Canadian Agency for Drugs and Technologies in Health (CADTH), Ottawa, Canada. 5CIET, Institute of Population
Health, University of Ottawa, Ottawa, Canada. 6Centre for Global Health, Institute of Population Health, University of Ottawa,
Ottawa, Canada. 7Epidemiology and Community Medicine, Ottawa Health Research Institute, Ottawa, Canada. 8Department of
Medicine, University of Ottawa, Ottawa, Canada
Contact address: George A Wells, Department of Epidemiology and Community Medicine, University of Ottawa, Room H1-1, 40
Ruskin Street, Ottawa, Ontario, K1Y 4W7, Canada. [email protected].
Editorial group: Cochrane Musculoskeletal Group.
Publication status and date: Edited (no change to conclusions), comment added to review, published in Issue 9, 2011.
Review content assessed as up-to-date: 13 November 2007.
Citation: Wells GA, Cranney A, Peterson J, Boucher M, Shea B, Welch V, Coyle D, Tugwell P. Alendronate for the primary and
secondary prevention of osteoporotic fractures in postmenopausal women. Cochrane Database of Systematic Reviews 2008, Issue 1. Art.
No.: CD001155. DOI: 10.1002/14651858.CD001155.pub2.
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
A B S T R A C T
Background
Osteoporosis is an abnormal reduction in bone mass and bone deterioration leading to increased fracture risk. Alendronate belongs to
the bisphosphonate class of drugs, which act to inhibit bone resorption by interfering with the activity of osteoclasts.
Objectives
To assess the efficacy of alendronate in the primary and secondary prevention of osteoporotic fractures in postmenopausal women.
Search strategy
We searched CENTRAL, MEDLINE and EMBASE for relevant randomized controlled trials published between 1966 to 2007.
Selection criteria
Women receiving at least one year of alendronate, for postmenopausal osteoporosis, were compared to those receiving placebo and/or
concurrent calcium/vitamin D. The outcome was fracture incidence.
Data collection and analysis
We undertook study selection and data abstraction in duplicate. We performed meta-analysis of fracture outcomes using relative risks
and a > 15% relative change was considered clinically important. We assessed study quality through reporting of allocation concealment,
blinding and withdrawals.
1Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Main results
Eleven trials representing 12,068 women were included in the review.
Relative (RRR) and absolute (ARR) risk reductions for the 10 mg dose were as follows. For vertebral fractures, a significant 45% RRR
was found (RR 0.55, 95% CI 0.45 to 0.67). This was significant for both primary prevention, with 45% RRR (RR 0.55, 95% CI 0.38
to 0.80) and 2% ARR, and secondary prevention with 45% RRR (RR 0.55, 95% CI 0.43 to 0.69) and 6% ARR. For non-vertebral
fractures, a significant 16% RRR was found (RR 0.84, 95% CI 0.74 to 0.94). This was significant for secondary prevention, with 23%
RRR (RR 0.77, 95% CI 0.64 to 0.92) and 2% ARR, but not for primary prevention (RR 0.89, 95% CI 0.76 to 1.04). There was a
significant 40% RRR in hip fractures (RR 0.60, 95% CI 0.40 to 0.92), but only secondary prevention was significant with 53% RRR
(RR 0.47, 95% CI 0.26 to 0.85) and 1% ARR. The only significance found for wrist was in secondary prevention, with a 50% RRR
(RR 0.50 95% CI 0.34 to 0.73) and 2% ARR.
For adverse events, we found no statistically significant differences in any included study. However, observational data raise concerns
regarding potential risk for upper gastrointestinal injury and, less commonly, osteonecrosis of the jaw.
Authors’ conclusions
At 10 mg per day, both clinically important and statistically significant reductions in vertebral, non-vertebral, hip and wrist fractures
were observed for secondary prevention (’gold’ level evidence, www.cochranemsk.org). We found no statistically significant results for
primary prevention, with the exception of vertebral fractures, for which the reduction was clinically important (’gold’ level evidence).
P L A I N L A N G U A G E S U M M A R Y
Alendronate for preventing fractures caused by osteoporosis in postmenopausal women
This summary of a Cochrane review presents what we know from research about the effect of alendronate for preventing fractures
(broken bones) caused by osteoporosis.
In women who have already been diagnosed with low bone density, putting them at risk for a fracture, or have already had a
fracture in the bones of their spine, alendronate:
- may prevent fractures in the spine, hip or wrist, or in bones other than the spine.
In women whose bone density is closer to normal, or who may not yet have had a fracture in the bones of their spine, alendronate:
- probably prevents fractures in the spine
- probably leads to no difference in fractures of the hip, wrist or bones other than the spine.
We often do not have precise information about side effects and complications. This is particularly true for rare but serious side effects.
Possible side effects may include digestive problems such as injury to the throat, esophagus and stomach and, less commonly, reduced
blood supply to the jaw bone, which causes the bone tissue to break down.
What is osteoporosis and what is alendronate?
Bone is a living, growing part of your body. Throughout your lifetime, new bone cells grow and old bone cells break down to make
room for the new, stronger bone. When you have osteoporosis, the old bone breaks down faster than the new bone can replace it. As
this happens, the bones lose minerals (such as calcium). This makes bones weaker and more likely to break even after a minor injury,
like a little bump or fall. Women are more likely to get osteoporosis after menopause.
Alendronate belongs to the class of drugs called bisphosphonates. It is a type of medication that slows down the cells that break down
the old bone.
2Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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The best estimate of what happens to women that have already been diagnosed with low bone density or have already had a
fracture in the bones of their spine:
Fracture of the spine
- 12 out of 100 women had a fracture when taking a placebo
- 6 out of 100 women had a fracture when taking alendronate
Fracture in the hip or wrist
- 2 out of 100 women had a fracture when taking a placebo
- 1 out of 100 women had a fracture when taking alendronate
Fractures in bones other than the spine
- 9 out of 100 women had a fracture when taking a placebo
- 7 out of 100 women had a fracture when taking alendronate
The best estimate of what happens to women whose bone density is closer to normal or who may not yet have had a fracture
in the bones of their spine:
Fracture of the spine
- 3 out of 100 women had a fracture when taking a placebo
- 1 out of 100 women had a fracture when taking alendronate
Fractures in bones other than the spine:
- 1 out of 100 women had a hip fracture when taking a placebo
- 1 out of 100 women had a hip fracture when taking alendronate
- 3 out of 100 women had a wrist fracture when taking a placebo
- 4 out of 100 women had a wrist fracture when taking alendronate
- 13 out of 100 women had a fracture somewhere other than the spine when taking a placebo
- 12 out of 100 women had a fracture somewhere other than the spine when taking alendronate
B A C K G R O U N D
Osteoporosis is in part a natural consequence of aging in post-
menopausal women (Hodsman 2002). It is a skeletal disorder char-
acterized by decreased bone mass, and deterioration in microar-
chitecture of bone resulting in an increased risk of fracture (NIH
Consensus 2001).
The most common consequences of osteoporosis are fractures of
the hip, wrist and vertebrae (Hodsman 2002). “Bone strength
reflects the integration of two main features: bone density and
bone quality” (Brown 2002). The clinical indicator of bone quality
is a patient’s history of a fragility fracture. A fragility fracture is a
fracture caused by an injury that would be insufficient to fracture
normal bone (e.g. a fall from a standing height or less)(Brown
2002). The preferred method of evaluating bone density is the
measurement of bone mineral density (BMD) of the spine and
hip by Dual Energy X-ray Absorptiometry (DXA), which can be
used to assess response to therapy (Hanley 2003).
The interpretation of BMD results is based on comparison of a
3Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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patient’s BMD with the mean value for a young adult population.
The “T-score” is the number of standard deviations (SDs) above
or below the mean BMD for normal young adults (Brown 2002).
The World Health Organization (WHO) Study Group on Os-
teoporosis defined osteoporosis as “a hip BMD level of more than
2.5 SDs below the mean BMD for young, white, adult women”
(WHO 1994). Using the WHO definition, approximately 30%
of postmenopausal women have osteoporosis (Kanis 1994; WHO
1994). It should be noted that there are limitations associated with
the WHO definition. The predictive value of BMD measurement
for fracture varies depending on the site selected, database used
for comparison and the technology used. Furthermore, T-scores
do not provide a good basis to establish comparable diagnostic
thresholds between different regions of interest and different bone
mass measurement techniques (Black 2001). As a result, between-
site and technique variability introduces potential for misclassifi-
cation and inappropriate treatment of some individuals.
Osteoporosis can be detected by BMD measurement or diagnosed
by presence of osteoporosis-related fractures. The presence of pre-
existing osteoporotic fractures is an important risk factor for future
fractures (Hodsman 2002). It is reported that 25% of women
aged 80 have had at least one vertebral fracture (Melton 1989).
Cauley 2000 demonstrated excess mortality in women who have
experienced a clinical vertebral fracture. The cumulative lifetime
fracture risk for a 50-year-old woman with osteoporosis is stated to
be as high as 60% (Cummings 1989). As a result, effective fracture
prevention would have a major impact on morbidity and a smaller
but important impact on mortality in these women.
Osteoporosis-related morbidity is associated with significant med-
ical and social consequences (Brown 2002). The major source of
morbidity and mortality from osteoporosis is attributed to hip
fractures. Hip fractures are not only associated with an increased
mortality risk, but also influence long-term function and indepen-
dence. Fifty percent of women who sustain a hip fracture do not
return to their previous functional state and become dependent
on others for their daily activities (Brown 2002). The mortality
associated with hip fractures in older women may be as high as
20% in the first year (Cauley 2000). This excess mortality may
not be directly attributable to the hip fracture, but to comorbid
conditions (Browner 1996; Cooper 1993).
Prevention and treatment of osteoporosis can be complex, due to
the multifactorial etiology of the disorder. Anabolic therapies di-
rected at increasing bone formation, such as teriparatide (recombi-
nant human parathyroid hormone (1-34))(Shukla 2003) are avail-
able and very expensive; however, most currently available osteo-
porosis drugs are anti-resorptive agents that act to decrease bone
turnover. Anti-resorptive drugs include the bisphosphonates (e.g.
etidronate, alendronate and risedronate). They are recommended
as first-line preventive agents in postmenopausal women with low
BMD, and as first-line agents for the treatment of postmenopausal
women with osteoporosis (Brown 2002).
Bisphosphonates are stable analogues of naturally occurring py-
rophosphates. The mechanism of action of these drugs is to in-
hibit bone resorption through their effects on osteoclast function
(Brown 2002). Bisphosphonates are poorly absorbed and avidly
taken up by bone on active sites of resorption. Alendronate is a sec-
ond generation nitrogen containing bisphosphonate which is ad-
ministered daily or once weekly (depending on formulation) and
does not impair bone mineralization at doses that maximally in-
hibit bone resorption (Rodan 1993). The recommended doses for
the prevention and treatment of osteoporosis in postmenopausal
women are 5 mg/day (35 mg/week) or 10 mg/day (70 mg/week).
Alendronate at 10 mg/day or greater, relative to control, has been
shown to increase bone mineral density by 7.48% (95% CI, 6.12
to 8.85) after two to three years of treatment in the lumbar spine;
5.60% (95%CI, 4.80 to 6.39) after three to for years in the hip
and 2.08% (95% CI, 1.53 to 2.63) after two to four years in the
forearm (Cranney 2002). At 5 mg/day, bone mineral density was
increased by 5.81% (95% CI, 4.32 to 6.29) after two to three
years in the spine, 4.64% (95%CI, 4.27 to 5.01) after three to
four years in the hip and 1.83% (95% CI, 1.47 to 2.20) after three
to four years in the forearm. (Cranney 2002).
O B J E C T I V E S
The aim of this systematic review was to assess the clinical effi-
cacy of alendronate in the primary and secondary prevention of
osteoporotic fractures in postmenopausal women receiving these
agents, compared with untreated women over a follow-up period
of at least one year.
M E T H O D S
Criteria for considering studies for this review
Types of studies
Randomized controlled trials (RCTs) with a duration of at least
one year were included in this review.
Types of participants
We included only post-menopausal women, and accepted both
primary and secondary prevention trials. A hierarchy was used
to define primary versus secondary prevention according to the
information available. We selected a definition of primary and
secondary prevention that gave more weight to study inclusion
criteria, than baseline statistics. That is, if the inclusion criteria
restricted the population to women whose bone density was at least
2 SD values below the peak bone mass, or the inclusion criteria
4Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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restricted the population to women who had experienced previous
vertebral compression fractures, then the trial was considered a
secondary prevention study. If such inclusion criteria were not
provided, then the baseline statistics were considered as follows: (a)
we considered the trial as primary prevention if the average T-score
(and SD) was such that it included women whose bone density
was within 2 SD of the mean, or if the prevalence of vertebral
fracture at baseline was less than 20%; and (b) when these data
were not available, we considered a trial as secondary prevention
if the average age was above 62 years.
Types of interventions
Treatment: Alendronate at any dose.
Comparators: No treatment (including placebo or calcium and/or
vitamin D). If the study used calcium and/or vitamin D controls,
these same treatments would have to be given concurrently in the
alendronate treatment groups.
Types of outcome measures
Incidence of fractures, including vertebral, non-vertebral, hip and
wrist fractures.
Search methods for identification of studies
The Cochrane Collaborative approach for identifying random-
ized controlled trials (RCTs) as described by Dickersin 1994, and
modified for the Cochrane Musculoskeletal Group, guided our
literature search. We searched the Cochrane Central Register of
Controlled Trials (CENTRAL), MEDLINE® (1966 to Novem-
ber 2004), Current Contents® and citations of relevant articles.
No language restrictions were applied to the search strategy. The
actual literature search was conducted in three stages. The first
stage was the basis for our systematic review published in 2002
(Cranney 2002) and the second and third stages involved updat-
ing the search. The first search, for the period 1966-99, included
CENTRAL, MEDLINE®, EMBASE® and Current Contents®.
This was followed by a MEDLINE® search for the time period
1999-November 2004. This MEDLINE search was confirmed by
a parallel literature search that was conducted for a companion
bisphosphonate economic report (CADTH 2006). For the final
update (2004 - February 2007), we searched CENTRAL, MED-
LINE and EMBASE.
Literature search for MEDLINE using OVID interface
1. osteoporosis, postmenopausal/
2. osteoporosis/
3. osteoporosis.tw.
4. exp bone density/
5. bone loss$.tw.
6. (bone adj2 densit$).tw.
7. or/2-6
8. menopause/
9. post-menopaus$.tw.
10. postmenopaus$.tw.
11. or/8-10
12. 7 and 11
13. 1 or 12
14. alendronate/
15. alendronate.tw,rn.
16. fosamax.tw.
17. aminohydroxybutane bisphosphonate.tw.
18. or/14-17
19. 13 and 18
20. meta-analysis.pt,sh.
21. (meta-anal: or metaanal:).tw.
22. (quantitativ: review: or quantitativ: overview:).tw.
23. (methodologic: review: or methodologic: overview:).tw.
24. (systematic: review: or systematic: overview).tw.
25. review.pt. and medline.tw.
26. or/20-25
27. 19 and 26
28. clinical trial.pt.
29. randomized controlled trial.pt.
30. tu.fs.
31. dt.fs.
32. random$.tw.
33. (double adj blind$).tw.
34. placebo$.tw.
35. or/28-34
36. 19 and 35
Data collection and analysis
Selection of studies
Two reviewers examined each title generated from the search and
identified potentially eligible articles, for which we obtained the
abstracts. For abstracts consistent with study eligibility, the full
article text was obtained. Overall, we only considered for inclusion
studies for which findings were published, either as full article or
abstract.
Data abstraction strategy
Two independent reviewers abstracted all information and data
using standardized data abstraction forms, with a third reviewer
verifying the data. Abstraction included information on pertinent
methodological aspects of the study design, characteristics of the
participants, the specific dose of the study drug used and the out-
comes assessed (e.g. number of vertebral, non-vertebral, hip and
wrist fractures). For fracture data, we considered all reported frac-
tures (whether clinical or radiographic).
For the yearly data, our unit of analysis was number of patients
sustaining a fracture. If an article reported yearly data, we used
the time points available. For baseline denominators, we used the
5Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
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same baseline denominator for each time point. For follow-up
denominators, we used any yearly follow-up number of patients
reported in the article, if available. If these were not available,
we assumed a uniform drop-out rate for each year and calculated
the denominators by determining the proportion of subjects that
would have remained at the end of the year in question based
on the number of withdrawals over the course of the study. If
an article reported only end of study outcomes, these were used
for our analysis with the exception of outcomes for which the
numerator was zero for both treatment groups. In these instances,
we included the outcome (with any necessary adjustments for
follow-up denominators) for the earlier years in the duration of the
study. For example, if a trial reported zero hip fractures for both
treatment arms at the end of year three, we would also include in
our analysis zero hip fractures for that trial at years one and two.
For person year data, the unit of analysis, if available, was number
of fractures. When these data were not available (i.e. in the major-
ity of cases), we used the number of women sustaining a fracture.
For denominators, we multiplied the number of women followed
by the length of the study. For radiographic vertebral fractures, we
used the number of women with available radiographs, if the num-
ber was reported in the article. For clinical fractures, we estimated
the number of women followed over the duration of the study by
taking the mean of the baseline and follow-up denominators.
Strategy for quality assessment
Two reviewers assessed each eligible RCT for quality based on
allocation concealment. Research has shown that lack of adequate
allocation concealment is associated with bias (Higgins 2005), and
studies can be judged on the method of allocation concealment.
The method for assigning participants to interventions should be
robust against patient and clinician bias, and its description should
be clear. The reviewers were required to indicate whether allocation
concealment was adequate (A), unclear (B), or inadequate (C) as
per The Cochrane Collaboration criteria as follows.
Adequate: The following are some approaches that can be used to
ensure adequate concealment schemes: centralized or pharmacy-
controlled randomization, pre-numbered or coded identical con-
tainers which are administered serially to participants; on-site com-
puter system combined with allocations kept in a locked unread-
able computer file that can be accessed only after the characteris-
tics of an enrolled participant have been entered or sequentially
numbered; or sealed, opaque envelopes. Other approaches may
include those similar to ones listed previously, along with reassur-
ance that the person who generated the allocation scheme did not
administer it.
Inadequate: Approaches to allocation concealment that are con-
sidered inadequate include: alternation, use of case record num-
bers, dates of birth or day of the week and any procedure that is
entirely transparent before allocation, such as an open list of ran-
dom numbers.
Unclear: When studies do not report any concealment approach,
adequacy should be considered unclear. Examples include merely
stating that a list or table was used, only specifying that sealed en-
velopes were used and reporting an apparently adequate conceal-
ment scheme in combination with other information that leads
the reviewer to be suspicious.
In addition, blinding and loss to follow-up were assessed.
Data analysis
For the analysis of fractures (i.e. vertebral, non-vertebral, hip and
wrist), the relative risk (RR) of fracture was calculated. The meth-
ods we used for pooling the results are described elsewhere (Fleiss
1993). The pooled or weighted RRs, using the general inverse vari-
ance method for the weights were calculated. For the pooled re-
sults, site-specific 95% confidence intervals (CIs) were calculated
for vertebral, non-vertebral, hip and wrist fractures, and we tested
for association using a chi-square test procedure, taking P value
< 0.05 for presence of statistical association. Statistically signifi-
cant risk reductions were considered to be clinically important if
a 15% or greater relative benefit was shown. We also tested for
homogeneity using a chi-square test procedure, taking the specific
cut-off for presence of statistical heterogeneity as P value = 0.10 (
Fleiss 1993). In the event of significant heterogeneity, a random-
effects model was used.
If the relative risk reduction (RRR) was significant (P value <
0.05), then the absolute risk reduction (ARR) and number needed
to treat (NNT) were calculated. For these calculations, we based
the five-year risk of fracture in the untreated population on the
FRACTURE Index (FI)(Black 2001), and the lifetime and five-
year age-specific risks in the untreated population on the model by
Doherty et al. (Doherty 2001) for predicting osteoporotic fractures
in postmenopausal women (Figure 1; Figure 2; Figure 3; Figure
4).
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Figure 1. Models for fracture risk in postmenopausal women: FRACTURE Index
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Figure 2. Five year risk of fracture by Quintiles of the FRACTURE Index: Assessment with bone mineral
density
Figure 3. Five year risk of fracture by Quintiles of the FRACTURE Index: Assessment without bone mineral
density
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Figure 4. Estimated five year age-specific risks of first and subsequent osteoporotic fractures (from Doherty
et al 2001)
Trials varied as to the length of treatment (e.g. one to four years)
and the number of patients available for study at the start of treat-
ment (i.e. baseline denominator) compared to those available at
different time points during the trial (i.e. follow-up denomina-
tors). The base case taken for the review of fractures considered
the data available for the longest period of time for the treatment
in the trial (i.e. “all years”) and used the baseline denominators for
the number of patients in the trial.
Data was initially pooled broadly across primary and secondary
trials. The overall analysis was also considered using person-years
of observation. In addition, we conducted subgroup analysis for:
1) primary versus secondary, 2) treatment duration and 3) treat-
ment dose. Furthermore, we conducted sensitivity analysis for:
1) baseline denominators versus follow-up denominators, 2) fixed
versus random effects model and 3) baseline vertebral fracture rate.
For the last sensitivity analysis, recall that the vertebral fracture
criteria for a trial to be considered secondary was a prevalence of
vertebral fracture at baseline of greater than 20%. A sensitivity
analysis using different vertebral fracture rates (i.e. 100%, > 80%,
> 60%, > 40%, > 20%) without the BMD and age criteria was
conducted. Such sensitivity analysis allowed evaluating whether
the effect of bisphosphonates on the secondary prevention of os-
teoporotic fractures varied, depending on how strictly secondary
prevention was defined.
Grading of evidence
We graded results for the primary analyses using the system de-
scribed in Evidence-based Rheumatology (Tugwell 2004), as recom-
mended by the Musculoskeletal Group.
Platinum:
To achieve the platinum level of evidence, a published systematic
review that has at least two randomized controlled trials each sat-
isfying the following is required:
- sample sizes of at least 50 per group - if these do not find a
statistically significant difference, they are adequately powered for
a 20% relative difference in the relevant outcome;
- blinding of patients and assessors for outcomes;
- handling of withdrawals > 80% follow up (imputations based on
methods such as Last Observation Carried Forward (LOCF) are
acceptable);
- concealment of treatment allocation.
Gold:
The gold level of evidence requires at least one randomized clinical
trial meeting all of the following criteria for the major outcome(s)
as reported:
- sample sizes of at least 50 per group - if they do not find a
statistically significant difference, they are adequately powered for
a 20% relative difference in the relevant outcome;
- blinding of patients and assessors for outcomes;
- handling of withdrawals > 80% follow up (imputations based on
methods such as LOCF are acceptable);
- concealment of treatment allocation.
Silver:
The silver level of evidence requires a randomized trial that does
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not meet the above criteria for gold or platinum ranking, or ev-
idence from at least one study of non-randomized cohorts that
did and did not receive the therapy, or evidence from at least one
high-quality case-control study. A randomized trial with a ’head-
to-head’ comparison of agents would be considered silver level
ranking unless a reference were provided to a comparison of one
of the agents to placebo showing at least a 20% relative difference.
Bronze:
The bronze level of evidence requires at least one high-quality case
series without controls (including simple before/after studies in
which patients act as their own control) or a conclusion derived
from expert opinion based on clinical experience without reference
to any of the foregoing (for example, argument from physiology,
bench research or first principles).
Clinical relevance tables
Clinical relevance tables were compiled under “additional tables”
to improve the readability of the review. Results were presented
within the context of both the study population and moder-
ate-/high-risk women from the population at large. The num-
ber needed to treat (NNT) was calculated using the relative risk
(RR) in combination with either the risk of fracture in the control
group, or the five-year FRACTURE Index (Black 2001). To do
this, the Visual Rx NNT calculator (Cates 2004) was used. The
weighted absolute risk difference was calculated using the risk dif-
ference (RD) statistic in RevMan and RR-1 was used to calculate
the relative percent change (Table 1; Table 2).
In addition, for the outcomes of vertebral and hip fractures we
prepared Summary of Findings tables using the GRADE criteria
from the GRADE working group (GRADE 2004), (Figure 5;
Figure 6).
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Figure 5. Summary of Findings for Primary Prevention
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Figure 6. Summary of Findings for Secondary Prevention
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R E S U L T S
Description of studies
See: Characteristics of included studies; Characteristics of excluded
studies.
Quantity of research available
The literature search revealed 1203 citations as depicted in Figure
7. Of these, 85 articles were retrieved for further review. A total of
74 articles were excluded for various reasons, including lack of ap-
propriate control group (19)(Black 2003; Body 2002; Chailurkit
2003; Davas 2003; Evio 2004; Iwamoto 2004; Kushida 2004;
Luckey 2004; Palomba 2002; Rittmaster 2000; Rizzoli 2002;
Rozkydal 2003; Sahota 2000; Sambrook 2004a; Schnitzer 2000;
Simon 2002; Sosa 2002; Tiras 2000; Vasikaran 1995); lack of
fracture outcome (25)(Aki 2003; Boivin 2000; Bouxsein 1999;
Chailurkit 2003; Chavassieux 1997; Cummings 2000; Dobnig
2006; Gonnelli 2002; Ho 2005; Johnell 2002; Kung 2000; Lau
2000; McClung 1998; Nenonen 2005; Ravn 1999a; Ravn 1999b;
Rhee 2006; Rossini 2000; Schneider 1999; Stepan 1999; Tutuncu
2005; Uusi-Rasi 2003; van der Poest 2000; Yen 2000; Yildirim
2005); lack of appropriate fracture data (i.e. reported as adverse
events or unspecified)(8), (Adami 1995; Bell 2002; Bone 2000;
Bonnick 1998; Downs 2000; Greenspan 2003; Hosking 2003;
Murphy 2001); lack of randomization (2), (Heijckmann 2002;
Sawka 2003); extension/discontinuation studies (6)(Bone 2004;
Greenspan 2002a; McClung 2004; Ravn 1999c; Ravn 2000;
Sambrook 2004b); duplicate report or earlier report of another
study (7)(Adami 1993; Bettembuk 1999; Black 2000; Devogelaer
1996; Hochberg 1999; Seeman 1999; Tucci 1996); duration
of therapy less than one year (7)(Cheng 2002; Chesnut 1993;
Greenspan 2002b; Harris 1993; Malavolta 1999; Payer 2000;
Rossini 1994). If we found duplicate reports of the same study in
preliminary abstracts and articles, we analyzed the data from the
most complete data set. In total, 11 trials met the selection criteria
for inclusion in this report (Ascott Evans 2003, Black 1996; Bone
1997; Chestnut 1995; Cummings 1998; Durson 2001; Greenspan
2002; Greenspan 1998; Hosking 1998; Liberman 1995; Pols
1999).
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Figure 7. Summary of literature search for alendronate
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Trial characteristics
The characteristics of the 11 selected trials are provided in the
’Characteristics of included studies’ table. A total of 12,068 women
were enrolled; of these, 5525 received placebo. Three trials were
in primary prevention (Ascott Evans 2003; Cummings 1998;
Hosking 1998), and the other eight involved women with low
BMD on densitometry and/or high prevalence of vertebral frac-
ture (Black 1996; Bone 1997; Chestnut 1995; Durson 2001;
Greenspan 2002; Greenspan 1998; Liberman 1995; Pols 1999).
Three trials (including the largest secondary prevention trial--the
Fracture Intervention Trial or FIT), used an initial dose of 5 mg and
then switched to 10 mg for the final years (Black 1996; Cummings
1998; Greenspan 1998). Two trials (Bone 1997; Hosking 1998)
evaluated only doses of 5 mg or less, four trials (Ascott Evans 2003;
Durson 2001; Greenspan 2002; Pols 1999) used only the 10 mg
dose and two trials (Chestnut 1995; Liberman 1995) evaluated 5,
10 and 20 mg doses. For some endpoints, studies which admin-
istered both 5 and 10 mg did not report the results separately by
dose (Black 1996; Cummings 1998; Greenspan 1998; Liberman
1995 ). To err on the conservative side, these endpoints were in-
cluded in the 10 mg analysis.
Length of follow up ranged from one to four years, and mean age
was 53 to 78 years. Eight trials excluded women with a history of
gastrointestinal disease (Black 1996; Bone 1997; Cummings 1998;
Durson 2001; Greenspan 2002; Hosking 1998; Liberman 1995;
Pols 1999) and three trials evaluated fractures as the stated primary
outcome (Black 1996; Cummings 1998; Durson 2001). All trials
administered at least 500 mg of calcium to all patients and vitamin
D, at daily doses ranging from 125-400 IU, was administered
in four trials (Black 1996; Cummings 1998; Greenspan 2002;
Greenspan 1998). We did not include data from the HRT arm of
the Hosking et al trial (Hosking 1998).
Risk of bias in included studies
Four trials concealed allocation (Black 1996; Bone 1997;
Cummings 1998; Hosking 1998) and for the remainder it was
unclear. Two trials achieved a loss to follow up of less than 5%
(Black 1996; Cummings 1998); five trials had losses to follow up
from 5% to 20% (Ascott Evans 2003; Chestnut 1995; Hosking
1998; Liberman 1995; Pols 1999); three trials had losses to follow
up over 20% (Bone 1997; Durson 2001; Greenspan 1998) and
one trial did not report losses to follow up (Greenspan 2002). All
studies but one were double blind (Durson 2001).
Effects of interventions
Effect on fractures
A summary of the overall review of fractures for the base case (i.e.
the longest treatment duration and use of the baseline denomina-
tors for the number of patients in the trial) for the standard 10
mg dose of alendronate is provided in Figure 8. In general, for
vertebral, non-vertebral, hip and wrist fractures, the pooled esti-
mate of the RR was significant for secondary prevention but not
for primary prevention (with the exception of vertebral fractures).
Figure 8. Weighted relative risk (RR) of fracture after alendronate (10 mg)
15Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
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Vertebral fractures
Vertebral fractures were reported in eight of 11 trials (Ascott Evans
2003; Black 1996; Bone 1997; Hosking 1998; Chestnut 1995;
Cummings 1998; Durson 2001; Liberman 1995). In two trials, no
fractures occurred in either treatment group (Ascott Evans 2003;
Chestnut 1995) and two trials (Bone 1997; Hosking 1998) eval-
uated only the 5 mg dose The pooled estimate of RR of verte-
bral fractures from the four trials (Black 1996; Cummings 1998;
Durson 2001; Liberman 1995) that could be analyzed for the 10
mg dose demonstrated a reduction (45%) in vertebral fractures
(RR 0.55, 95%, CI 0.45 to 0.67). For details, please refer to Figure
8 and Comparison 01.01. This supports a fracture risk reduction
with alendronate and results were consistent across the four trials
(P = 0.61). There was a significant reduction in vertebral fractures
for both primary and secondary prevention trials. Estimates for
the risk reduction were similar for the primary (RR 0.55, 95%
CI, 0.38 to 0.80) and secondary (RR 0.55, 95% CI 0.43 to 0.69)
prevention trials.
Corresponding to the significant RRR of 45% for the primary
or secondary prevention of vertebral fractures, the absolute mea-
sures ARR and NNT of the 5-year risk of vertebral fracture after
treatment with alendronate were calculated for different levels of
increasing risk as given by the FI. Results are provided in Figure
9, as well as for increasing age in Figure 10. For the illustrative
case of the patient with a FI of 6-7, the ARR in vertebral fracture
was 3.2% (i.e. a reduction in risk from 7.1% to 3.9%) and the
NNT was 31 (i.e. 31 patients would need to be treated to avoid
one vertebral fracture). Across the range of increasing FI risk, the
ARR for vertebral fracture ranged from 0.5% to 5.0%, and the
NNT to avoid one vertebral fracture ranged from 200 to 20. For
the illustrative patient in the age group 60-64 years, the ARR for
the first vertebral fracture was 0.5% (i.e. a reduction in risk from
1.0% to 0.55%) and the NNT was 222 patients treated to avoid
the first fracture. The ARR for a subsequent fracture was 4.4%
(i.e. a reduction in risk from 9.7% to 5.3%) and the NNT was
23 patients treated to avoid one subsequent fracture. For increas-
ing age, the 5-year age-specific ARR for the first vertebral fracture
increased from 0.1% for the youngest age group (50-54 years) to
2.1% in the highest age group (90+ years). Accordingly, the NNT
decreased from 1111 to 47. For the subsequent fracture, ARR in-
creased from 0.2% to 12.6% and the NNT decreased from 444
to 8.
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Figure 9. Five year FRACTURE Index specific risk of fracture after alendronate (10 mg)
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Figure 10. Five year age-specific fisk of first and subsequent fracture after alendronate (10 mg)
Non-vertebral fractures
Non-vertebral fractures were reported in nine trials (Ascott Evans
2003; Black 1996; Bone 1997; Chestnut 1995; Cummings 1998,
Hosking 1998; Greenspan 1998; Liberman 1995; Pols 1999).
One trial did not report fractures separately by treatment groups
(Chestnut 1995); one trial reported that no fractures occurred in
either treatment group (Ascott Evans 2003) and two trials evalu-
ated only the 2.5 and 5 mg doses. (Bone 1997; Hosking 1998).
The pooled estimate of the RR of non-vertebral fractures from
the five trials (Black 1996; Cummings 1998; Greenspan 1998;
Liberman 1995; Pols 1999) that could be analyzed for the 10 mg
dose demonstrated a significant reduction (16%) in non-vertebral
fractures (RR: 0.84, 95% CI 0.74 to 0.94). Details can be found
in (Figure 8 and Comparison 02.01) and results were consistent
across the five trials (p = 0.29). Although the primary and sec-
ondary prevention trials differed in significance of the reduction in
risk of non-vertebral fractures, the non-significant reduction (RR
0.89, 95% CI 0.76 to 1.04) in the one primary was not clearly
different from the significant reduction (RR 0.77, 95% CI 0.64
to 0.92) in the four secondary prevention trials.
Corresponding to the significant RRR of 23% for the secondary
prevention of non-vertebral fractures, the absolute measures ARR
and NNT of the five-year risk of non-vertebral fracture after treat-
ment with alendronate were calculated for different levels of in-
creasing risk as measured by the FI (Figure 9) and for increasing age
(Figure 10). For the illustrative case of the patient with a FI of 6-
7, the ARR in non-vertebral fracture was 4.6% (i.e. a reduction in
risk from 19.8% to 15.2%) and the NNT was 22 (i.e. 22 patients
need to be treated to avoid one non-vertebral fracture). Across the
range of increasing FI risk, ARR for non-vertebral fracture ranged
from 2.0% to 6.3% and NNT to avoid one non-vertebral frac-
ture ranged from 50 to 16. For the illustrative patient in the age
group 60-64 years, the ARR for the first non-vertebral fracture
was 0.7% (i.e. a reduction in risk from 3.1% to 2.4%) and the
NNT was 140 patients treated to avoid the first fracture. The ARR
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for a subsequent fracture was 1.4% (i.e. a reduction in risk from
6.2% to 4.8%) and the NNT was 70 patients treated to avoid one
subsequent fracture. For increasing age, the five-year age-specific
ARR for the first non-vertebral fracture increased from 0.4% for
the youngest age group (50-54 years) to 8.1% in the highest age
group (90+ years) and the NNT decreased from 272 to 12. The
ARR for subsequent fracture increased from 0.6% to 8.7% and
the NNT decreased from 167 to 12.
Hip fractures
Hip fractures were reported in seven trials (Ascott Evans 2003;
Black 1996; Cummings 1998; Greenspan 2002; Greenspan 1998;
Liberman 1995; Pols 1999), with one trial reporting that no frac-
tures occurred in either treatment group (Ascott Evans 2003). The
pooled estimate of the RR of hip fractures from the six trials re-
sulted in a significant reduction (39%) in hip fractures (RR 0.61,
95% CI 0.40 to 0.92) as presented in (Figure 8 and Compari-
son 03.01). The results were consistent across the six trials (p =
0.84). The reduction in the risk of hip fractures for the one pri-
mary prevention trial (Cummings 1998) was not significant (RR
0.79, 95% CI 0.44 to 1.44) compared to the significant reduction
demonstrated by the five secondary prevention trials (RR 0.47,
95% CI 0.26 to 0.85).
Corresponding to the significant RRR of 53% for the secondary
prevention of hip fractures, the absolute measures: ARR and NNT
of the five-year risk of hip fracture after treatment with alendronate
were calculated for different levels of increasing risk as measured
by the FI. Results are provided in Figure 9 in addition to those for
increasing age in Figure 10. For the illustrative case of the patient
with a FI of 6-7, the ARR in hip fracture was 2.1% (i.e. a reduction
in risk from 3.9% to 1.8%) and the NNT was 48 (i.e. 48 patients
need to be treated to avoid one hip fracture). Across the range of
increasing FI risk, the ARR for hip fracture ranged from 0.2% to
4.6% and the NNT to avoid one hip fracture ranged from 500
to 22. For the illustrative patient in the age group 60-64 years,
the ARR for the first hip fracture was 0.1% (i.e. a reduction in
risk from 0.2% to 0.1%) and the NNT was 943 patients treated
to avoid the first fracture. The ARR for a subsequent fracture
was 0.1% (i.e. a reduction in risk from 0.2% to 0.1%) and the
NNT was 943 patients treated to avoid one subsequent fracture.
For increasing age, the five-year age-specific ARR for the first hip
fracture increased from less than 0.05% for the youngest age group
(50-54 years) to 11.1% in the highest age group (90+ years) and
the NNT decreased from more than 272 to 9. For the subsequent
fracture, the ARR increased from less than 0.05% to 12.1% and
the NNT decreased from more than 472 to 8.
Wrist fractures
Wrist fractures were reported in five trials (Black 1996; Cummings
1998; Greenspan 1998; Liberman 1995; Pols 1999) and one trial
(Ascott Evans 2003) reported that no fractures occurred in either
treatment group. Results were not consistent across the five trials
which reported wrist fractures (p = 0.0007)(Figure 11). The pooled
estimate of the RR of wrist fracture from these five trials resulted in
a non-significant reduction in fractures, either using the random
effects (RR 0.68, 95% CI 0.34 to 1.37)(Figure 8) or fixed effect
(RR 0.83, 95%CI 0.65, 1.05) approach. We also could not identify
a statistically significant effect of alendronate when used for the
primary prevention of wrist fractures (RR 1.19, 95%CI 0.87 to
1.62)(Figure 8 and Comparison 04.01). In the case of the four
secondary prevention trials, a statistically significant effect was
observed (RR 0.50, 95%CI 0.34 to 0.73).
Figure 11. Weighted relative risk of fracture after alendronate (10 mg) by years of treatment
19Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
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Additional analysis
Person years
Results were similar for vertebral, non-vertebral, hip and wrist
fractures when person years were used, as illustrated in Figure 12.
Notably, the pooled estimates of the RR for the secondary pre-
vention trials all showed a significant risk reduction of fracture for
all fractures sites. Due to lack of consistency among the trials, a
random-effects estimate was used for the pooled estimate for ver-
tebral fractures; however, for wrist fractures, there was no incon-
sistency among the secondary prevention trials. The risk estimates
obtained from the one primary prevention trial for vertebral frac-
ture remained significant although results were non-significant for
the other fracture sites.
Figure 12. Weighted relative risk (RR) of fracture after alendronate (10 mg): Person years
Subgroup analysis
Treatment duration
There were no trends over years of treatments that deviated from
the overall RR estimates (Figure 11 and Comparisons 05.01;
06.01; 07.01; 08.01; 09.01), with the possible exception of hip
fracture risk reduction being greater in later years.
Treatment dose
For the 5 mg dose of alendronate, fracture data were available for
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vertebral and non-vertebral sites for secondary prevention trials,
as well as non-vertebral for primary prevention. (Figure 13; Figure
14; Figure 15; Comparison 12.01) For vertebral fractures, the
decrease in risk of fracture was statistically significant and there
was a further slight decrease in risk with the 5 mg dose (RR 0.40,
95%CI 0.29 to 0.55), compared to 10 mg (RR 0.55, 95%CI 0.43
to 0.69). For non-vertebral fractures, no significant difference was
found.
Figure 13. Weighted relative risk of fractrue after alendronate by dose
21Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
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Figure 14. Weighted relative risk of fracture after alendronate by dose: Person years
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Figure 15. Weighted relative risk of fracture after alendronate by years of treatment and dose
Sensitivity analysis
Baseline versus follow-up denominators
By using the data available for longest treatment duration, standard
dose of alendronate (10 mg) and follow-up denominators for the
number of patients in the trials, a summary of the overall review
of fractures was prepared (Figure 16). These data are also provided
by years of treatment. (Figure 17). The pooled estimates of the
RR of fracture after alendronate were essentially the same as those
obtained using the baseline denominators.
23Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
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Figure 16. Weighted relative risk of fracture after alendronate by dose: Follow-up denominators
24Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
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Figure 17. Weighted relative risk of fracture after alendronate by years of treatment and dose: Follow-up
denominators
Random versus fixed effects model
There were a few instances where heterogeneity of the trial results
was such that a random-effects model was required. In general,
results obtained using the random- and fixed-effects models were
similar.
Baseline vertebral fracture rate
Using different baseline vertebral fracture rates (i.e. 100%, > 80%,
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> 60%, > 40%, > 20%) for defining secondary trials, a summary
of the overall review of fractures was prepared (Figure 18). For
vertebral fractures, the pooled estimates of the RR of fracture after
alendronate were essentially the same as those obtained using the
definition of secondary trials with the > 20% baseline fracture rate.
Although the result for non-vertebral and hip fractures became
non-significant when the criteria increased from > 20% to > 40%
and > 40% to > 60% respectively, the relative risk of fracture was
exactly the same but the confidence intervals were now slightly
wider with the exclusion of the study by Liberman et al (Liberman
1995) for non-vertebral fractures and Greenspan et al (Greenspan
2002) for hip fractures. For wrist fractures, the non-significant
result was now significant when a > 20% baseline fracture rate
was used (without the BMD and age criteria) since a fixed-effects
model could now be used.
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Figure 18. Weighted relative risk (RR) of fracture after alendronate (10 mg): sensitivity analysis by baseline
prevalent vertebral fracture rate
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Adverse events
A summary of the adverse drug events reported in the 11 random-
ized placebo-controlled trials of alendronate is provided in Figure
19, Figure 20, Figure 21 and Figure 22. In general, the reported
events were similar between alendronate and placebo. In partic-
ular, there were seven studies (Ascott Evans 2003; Black 1996;
Cummings 1998; Greenspan 1998; Greenspan 2002; Hosking
1998; Pols 1999) reporting ’any upper gastrointestinal events’ re-
sulting in an overall RR 1.03 (95% CI 0.98 to 1.08) and two stud-
ies (Black 1996; Cummings 1998) reporting ’esophageal ulcer’,
resulting in an overall RR 1.16 (95% CI 0.39 to 3.45).
Figure 19. Summary of adverse drug events reported in randomized placebo-controlled trials of
alendronate (part 1)
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Figure 20. Summary of adverse drug events reported in randomized placebo-controlled trials of
alendronate (part 2)
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Figure 21. Summary of adverse drug events reported in randomized placebo-controlled trials of
alendronate (part 3)
Figure 22. Summary of adverse drug events reported in randomized placebo-controlled trials of
alendronate (part 4)
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Toxicity and withdrawals
Discontinuations due to adverse events or dropouts overall were
available and analyzed for six (Ascott Evans 2003; Black 1996;
Bone 1997; Cummings 1998; Durson 2001; Pols 1999) and five
(Ascott Evans 2003; Durson 2001; Greenspan 1998; Hosking
1998; Pols 1999) of the alendronate trials respectively. The pooled
estimate demonstrated no statistical difference between alen-
dronate and placebo for the risk of discontinuing medication due
to adverse events (RR 0.95, 95% CI 0.83 to 1.09) or for dropouts
overall (RR 1.10, 95% CI 0.94 to 1.29)(Comparison 13.01 and
13.02). Results were consistent across the trials.
D I S C U S S I O N
Summary of results
Based on the longest treatment duration and use of baseline de-
nominators for the number of patients in the included trials, the
main benefit of alendronate was found to be in the secondary pre-
vention of osteoporotic fractures. At a dose of 10 mg per day, al-
endronate results in a statistically significant and clinically impor-
tant reduction in vertebral, non-vertebral, hip and wrist fractures
(gold level evidence). We also found that the use of alendronate 10
mg per day for the primary prevention of osteoporotic fractures is
not associated with statistically significant reductions in risk, with
the exception of vertebral fractures for which the reduction was
clinically important (gold level evidence).
Secondary analyses showed that a dose of 5 mg, for secondary pre-
vention resulted in a statistically significant and clinically impor-
tant reduction in vertebral fractures that is comparable to that of
the 10 mg dose (RR 0.40, 95% CI 0.27 to 0.52 versus RR 0.55,
95% CI 0.43 to 0.69). It is worth noting that these results were
driven primarily by the large Black trial (Black 1996). In Black,
the 5 mg data represented the first two years of follow up of the
treatment group which was switched to 10 mg for the third year.
No trials were available to assess the effectiveness of the 5 mg dose
for the primary prevention of vertebral fractures. For non-verte-
bral fractures, no statistically significant reductions were shown for
primary or secondary prevention. There were no trials available to
assess the efficacy of the 5 mg dose for hip and wrist fractures.
There were no substantive differences in the results whether base-
line, end of study or person year denominators were used. Sensi-
tivity analyses indicated that there were no major differences based
on the percentage of baseline vertebral fractures. Further, no trends
were found for years of treatment.
Adverse drug events were similar between alendronate and placebo.
There were also no statistically significant difference in either the
rate of treatment discontinuation due to adverse events (RR 0.95,
95% CI 0.83 to 1.09) or the overall withdrawal rate (RR 1.10, 95%
CI 0.94 to 1.29), compared to placebo. Thus, it was concluded
that study participants tolerated their alendronate treatment. Al-
though no increased incidence of adverse effects was detected with
alendronate, external to the randomized controlled trials, concerns
exist regarding the potential risk of upper gastrointestinal events
and osteonecrosis of the jaw.
Study limitations
The results of this systematic review are believed to be robust, as
a comprehensive literature search was performed, inclusion and
exclusion criteria were specified and a rigorous data analysis was
conducted. A potential limitation of our approach may be that
the update search (i.e. 2000 to 2004) did not include non-MED-
LINE® indexed journals. Recent empirical evidence indicates that
this approach may have introduced a slight risk of bias into our
meta-analysis. On average, such bias is estimated to result in a
6% variation in the pooled results (Egger 2003; Sampson 2003).
Accordingly, given that the initial literature search (i.e. 1966 to
2000) was very extensive, the impact of only using MEDLINE®
for the search update is expected to be minimal, if any. This
was confirmed by a parallel literature search update (i.e. 1999
to July 2004) that was conducted for an economic report pub-
lished by The Canadian Agency for Drugs and Technologies in
Health (CADTH 2006). The search update included etidronate,
alendronate and risedronate (daily dose regimen only) in addi-
tion to teriparatide. A number of databases were searched (i.e.
the Cochrane Library, MEDLINE®, EMBASE®, BIOSIS Pre-
views®, Toxfile and PubMed) and no additional articles meeting
the inclusion criteria were identified.
While our methodology was robust, the results of our meta-anal-
ysis, however, are only as strong as the primary studies included.
In keeping with this, the main limitations with regard to study
quality were fracture assessment and classification, the lack of clar-
ity of the concealment of allocation and large losses to follow up
(primarily in the smaller studies).
A potential source of heterogeneity is the lack of uniform defini-
tion of non-vertebral fracture. While some researchers may use a
rather liberal definition (any fracture other than vertebral fracture),
others may use a more conservative definition which includes only
fractures of the hip, clavicle, humerus, wrist, pelvis or leg (Mayo
Clin Proc 2005). Another consideration is the fact that fracture
data was not the primary outcome for many of the trials. In par-
31Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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ticular, three of the 11 alendronate trials (Black 1996; Cummings
1998; Durson 2001) had fractures as the primary outcome. There
is another source of heterogeneity, and possible bias, related to
some of the secondary prevention studies. It concerns the inclu-
sion of participants with a low BMD but no proven fractures, and
the difficulty in discriminating between fracture types (traumatic
versus pathological).
Another methodological limitation concerns the approach used
for concealment of treatment allocation which was not reported
for most trials. Four of the 11 trials (Black 1996; Bone 1997;
Cummings 1998; Hosking 1998) concealed allocation, and for
the remainder it was unclear.
An additional limitation is the length of follow up in the studies.
It is difficult to extrapolate beyond the duration of the follow-up
trials in the review with respect to the long-term impact on frac-
tures. Ultimately, data from longer-term trials will help establish
if the effect on fractures is maintained, increased or diminished.
In regards to our own methodology, we acknowledge that the ap-
proach used to evaluate the effect of bisphosphonates over time
may result in some estimates that are not robust. In particular,
in order to determine the effect on the five-year risk of fracture,
we based our evaluation on the FRACTURE Index by Black et
al (Black 2001), and for lifetime and five-year age-specific risks,
we used an existing model from Doherty et al (Doherty 2001).
Although this latter approach allowed us to estimate the variation
in risks between younger and older postmenopausal women, these
estimates may be associated with a certain level of uncertainty.
Nonetheless, we believe such information may be useful to deci-
sion-makers.
Lastly, a limitation of evaluating data on adverse effects from sum-
mary meta-analyses is that participants in RCTs tend to be health-
ier, with fewer co-morbid diseases, and therefore the results may
not be generalizable to clinical practice. For alendronate, eight
trials (Black 1996; Bone 1997; Cummings 1998; Durson 2001;
Greenspan 2002; Hosking 1998; Liberman 1995; Pols 1999) ex-
cluded patients with pre-existing gastrointestinal (GI) disorders.
Furthermore, RCTs are underpowered for rare effects and meta-
analyses of these trials generally cannot provide conclusive infor-
mation pertaining to drug toxicity. In addition, the heterogeneity
of the adverse drug effects (ADEs) reported in the RCTs described
in this review, including their nature, low occurrence and way they
were assessed by investigators, made these improper for meta-anal-
ysis. Although a number of trials reported composite endpoints
such as “any GI event”, as well as a number of individual GI events,
only the two largest trials (Black 1996; Cummings 1998), for ex-
ample, specifically reported esophageal ulcers (an endpoint of par-
ticular interest, for which there were no statistically significant dif-
ferences between treatment and control). As well, the follow up
for the included trials, which ranged between one and four years,
does not allow for the assessment of long-term toxicity associated
with alendronate.
Recently, there have been concerns regarding the potential risk of
over suppressing bone turnover resulting in osteonecrosis of the
jaw (ONJ)(Khosla 2007; Woo 2006). Although the majority of
reported cases of ONJ have occurred in cancer patients receiv-
ing the intravenous bisphosphonates zolendrate or pamidronate
(at higher cumulative doses than used in the treatment of post-
menopausal osteoporosis), some osteoporosis patients receiving
oral bisphosphonates have developed the condition as well. In a
systematic review of cases reported in the medical literature, 13
of 368 bisphosphonate treated ONJ patients had received alen-
dronate and one risedronate (Woo 2006). Since that publication,
a review conducted by the American Society for Bone and Min-
eral Research (ASBMR) Task Force on Bisphosphonate-Associ-
ated ONJ has identified studies reporting a total of 67 cases (64
alendronate, two risedronate and one etidronate) among osteo-
porosis and Paget’s disease patients (Khosla 2007). Most notably,
an Australian study reported 30 of 114 ONJ cases related to al-
endronate (22 of whom were under treatment for osteoporosis)
and two related to risedronate. The median time to onset, for al-
endronate, was 24 months. The most common triggering factor
was dental extraction (Mavrokokki 2007). The ASBMR task force
has pointed out that the incidence of ONJ in the general popu-
lation not exposed to bisphosphonates is unknown, information
on the incidence of ONJ is rapidly evolving and that ,often, the
case ascertainment has been inadequate . They recommend that
a hierarchy of evidence quality, based on the completeness of in-
formation across seven categories related to diagnosis and history,
should be established for all future studies reporting cases of ONJ
(Khosla 2007).
No cases of ONJ were explicitly reported in any of the alendronate
trials in our review. As well, a recent 10-year follow up of patients
from the Black and Cummings trials (The Fracture Intervention
Trial Long-term Extension (FLEX) reported that no cases were
observed among the 662 women who were continued on alen-
dronate at 5 or 10 mg for a total of 10 years or the 437 women
who were switched to placebo following five years of alendronate
treatment (Black 2006). No difference between treatment groups
were found for any other adverse events in FLEX.
Finally, because RCTs are not designed to measure ADEs, partic-
ularly rare ones, it is common practice to include sources of infor-
mation other than RCTs. While some reviewers include ADEs re-
ported in observational studies, we elected to obtain information
from the Canadian Adverse Drug Reaction Monitoring Program
(CADRMP) (Health Canada 2005).
Generalizability of findings
Generalizability of our findings is limited by the controlled design
of the trials included in our review. Study participants were care-
fully selected in these trials, and so utilization of the drugs in real
32Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
INTERNAL U
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life may vary substantially from study conditions. Furthermore,
study participants were observed for periods of time varying from
one to four years. Consequently, while our results provide support
for efficacy (i.e. can the intervention have an effect on outcome?),
they may possibly only provide partial information on the long-
term effectiveness (i.e. does the intervention have an effect on out-
come?) of alendronate in preventing osteoporotic fractures.
From a safety perspective, we could not find any statistically signif-
icant difference in either the rates of adverse drug events or with-
drawal rates due to adverse drug events between patients receiv-
ing a bisphosphonate or patients receiving a placebo. However,
outside controlled trials, concerns exist regarding the safe use of
alendronate, for which esophageal ulcers and gastritis have been
reported (Kherani 2002). While such adverse events have mainly
been identified through case reports and endoscopic studies, simi-
lar concerns are also reflected in the proportions of gastrointestinal
adverse drug reactions associated with the use of bisphosphonates
reported to the CADRMP (Health Canada 2005). Indeed, GI ad-
verse drug reactions represented 38% of all reactions reported for
alendronate (Figure 23). These proportions should, however, be
interpreted with caution, as adverse drug reactions are reported
to CADRMP on a volunteer basis by health professionals, which
means that several reactions may be unreported. Indeed, it is es-
timated that less than 10% of adverse reactions are reported to
Health Canada (Health Canada 2005c). Also, a definite cause-
effect relationship has not been established for these adverse drug
reactions.
33Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Figure 23. Adverse drug reactions reported to CADRMP for etidronate, alendronate and risedronate
34Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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A U T H O R S ’ C O N C L U S I O N SImplications for practice
Alendronate demonstrated a clinically important benefit in the
secondary prevention of all osteoporotic fractures. At a dose of 10
mg per day, statistically significant reductions in vertebral, non-
vertebral, hip and wrist were observed. The secondary prevention
population was defined as having a bone density of at least 2 SD
values below peak bone mass or one or more vertebral compres-
sion fractures, or both. There were no statistically significant re-
ductions found for the primary prevention of osteoporotic frac-
tures, with the exception of vertebral fractures, for which the re-
duction was clinically important. No increased incidence of ad-
verse effects were detected with alendronate, but clinicians should
be aware that outside of randomized controlled trials, concerns
exist regarding the potential risk of upper gastrointestinal events
and, less commonly, osteonecrosis of the jaw.
The prevention of osteoporotic fractures is an important public
health intervention. This is particularly true for hip and clinical
vertebral fractures (i.e. fractures of the spine that present for med-
ical attention). The RR of death following such fractures is six- to
nine-fold greater in postmenopausal women aged 55 to 81 years
with low BMD, which represents a typical postmenopausal pop-
ulation (Cauley 2000). In most cases, the mortality increase re-
flects poor underlying health status and comorbidity, in addition
to the fracture itself (Cauley 2000). Osteoporotic fractures are also
associated with increase in morbidity, as it is reported that 50%
of women who sustain a hip fracture do not return to their usual
daily activities (Brown 2002), while 33% will require long-term
care. Accordingly, reducing the incidence of such fractures can po-
tentially increase the quality of life of patients with osteoporosis.
Such interventions may also potentially decrease mortality.
Implications for research
It has been suggested from clinical trials with the bisphosphonates
(Black 2000b; Harris 1999; McClung 2001) that their effect in
reducing non-vertebral fractures may be greater in patients with
lower BMD who initiate treatment. The existing data have not
fully resolved the question of whether important differences in
risk reduction across groups of patients with varying degrees of
osteoporosis exist. The impact of the bisphosphonates on the RR
of non-vertebral fractures in populations without osteoporosis also
merits further investigation. Additional research is needed to clar-
ify the role of bisphosphonates in the primary prevention of os-
teoporotic fractures. There is also a need for further post-market-
ing safety. Finally, research into combination therapy with higher
doses of vitamin D or anabolic agents would be merited as would
research concerning adherence to bisphosphonate therapy.
Given the morbidity consequences associated with osteoporotic
fractures, preventing their recurrence can potentially lessen the
need for community-based health services (e.g. home care). It may
also reduce or delay the demand for long-term care beds. However,
very little comparative information is currently available to sup-
port this (Hodsman 2002). There is also a lack of studies which
evaluated the effect of bisphosphonates on hospital admissions
(Hodsman 2002).
A C K N O W L E D G E M E N T S
Thank you to Lara Maxwell and Marie Andree Nowlan from the
Cochrane Musculoskeletal Group for their editorial assistance, and
Tamara Rader for her assistance with the Consumer Summary.
R E F E R E N C E S
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Black 1996 {published data only}∗ Black DM, Cummings SR, Karpf DB, Cauley JA,
Thompson DE, Nevitt MC, et al.Randomised trial of effect
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WB, Barrett-Connor E, Musliner TA, et al.Effect of
alendronate on risk of fracture in women with low bone
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Greenspan 2002 {published data only}
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Petruschke R, Wang L, et al.Tolerability of once-weekly
alendronate in patients with osteoporosis: a randomized,
double-blind, placebo-controlled study. [see comment].
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Hosking 1998 {published data only}∗ Hosking D, Chilvers CE, Christiansen C, Ravn P, Wasnich
R, Ross P, et al.Prevention of bone loss with alendronate
in postmenopausal women under 60 years of age. Early
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Liberman 1995 {published data only}
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Bell NH, et al.Effect of oral alendronate on bone mineral
density and the incidence of fractures in postmenopausal
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A, Santora AC, Study Group. Alendronate increases bone
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T, Hochberg MC, et al.Fracture risk reduction with
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Black 2003 {published data only}
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McGowan JA, Lang TF, et al.The effects of parathyroid
hormone and alendronate alone or in combination in
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the efficacy of teriparatide (recombinant human parathyroid
hormone (1-34)) with alendronate in postmenopausal
women with osteoporosis. [see comment]. Journal of
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Boivin 2000 {published data only}
Boivin GY, Chavassieux PM, Santora AC, Yates J, Meunier
PJ. Alendronate increases bone strength by increasing the
mean degree of mineralization of bone tissue in osteoporotic
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Bone 2000 {published data only}
Bone HG, Greenspan SL, McKeever C, Bell N, Davidson
M, Downs RW, et al.Alendronate and estrogen effects in
postmenopausal women with low bone mineral density.
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Bone 2004 {published data only}
Bone HG, Hosking D, Devogelaer JP, Tucci JR, Emkey
RD, Tonino RP, et al.Ten years’ experience with alendronate
for osteoporosis in postmenopausal women. [see comment].
New England Journal of Medicine 2004;350(12):1189–99.
36Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
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Bonnick 1998 {published data only}
Bonnick S, Rosen C, Mako B, DeLucca P, Byrned C, Melton
M. Alendronate vs calcium for treatment of osteoporosis in
postmenopausal women.. Bone 1998;350(5S):S476.
Bouxsein 1999 {published data only}
Bouxsein ML, Parker RA, Greenspan SL. Forearm bone
mineral densitometry cannot be used to monitor response
to alendronate therapy in postmenopausal women.
Osteoporosis International 1999;10(6):505–9.
Chailurkit 2003 {published data only}
Chailurkit LO, Jongjaroenprasert W, Rungbunnapun S,
Ongphiphadhanakul B, Sae-tung S, Rajatanavin R. Effect
of alendronate on bone mineral density and bone turnover
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B, Jongjaroenprasert W, Sae-tung S, Rajatanavin R.
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Chavassieux 1997 {published data only}
Chavassieux PM, Arlot ME, Reda C, Wei L, Yates
AJ, Meunier PJ. Histomorphometric assessment of the
long-term effects of alendronate on bone quality and
remodeling in patients with osteoporosis. Journal of Clinical
Investigation 1997;100(6):1475–80.
Cheng 2002 {published data only}
Cheng ZQ, Yin W, Fan JY, Ma TJ. [The efficacy
of alendronate in the prevention and treatment of
postmenopausal osteoporosis]. [Chinese]. Chung-Kuo i
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Sinicae 2002;24(3):306–9.
Chesnut 1993 {published data only}
Chesnut CH, Harris ST. Short term effect of alendronate on
bone mass and bone remodeling in postmenopausal women.
Osteoporosis International 1993;3(Suppl 3):S17–S19.
Cummings 2000 {published data only}
Cummings SR, Palermo L, Browner W, Marcus R, Wallace
R, Pearson J, et al.Monitoring osteoporosis therapy with
bone densitometry: misleading changes and regression to
the mean. Fracture Intervention Trial Research Group.
JAMA 2000;283(10):1318–21.
Davas 2003 {published data only}
Davas I, Altintas A, Yoldemir T, Varolan A, Yazgan A, Baksu
B. Effect of daily hormone therapy and alendronate use on
bone mineral density in postmenopausal women. Fertility
& Sterility 2003;80(3):536–40.
Devogelaer 1996 {published data only}
Devogelaer JP, Broll H, Correa-Rotter R, Cumming DC,
De Deuxchaisnes CN, Geusens P, et al.Oral alendronate
induces progressive increases in bone mass of the spine, hip,
and total body over 3 years in postmenopausal women with
osteoporosis. [erratum appears in Bone 1996 Jul;19(1):78].
Bone 1996;18(2):141–50.
Dobnig 2006 {published data only}
Dobnig H, Hofbauer LC, Viereck V, Obermayer-Pietsch
B, Fahrleitner-Pammer A, Dobnig H, et al.Changes in the
RANK ligand/osteoprotegerin system are correlated to
changes in bone mineral density in bisphosphonate-treated
osteoporotic patients. Osteoporosis International 2006;17(5):
693–703. [MEDLINE: 13]
Downs 2000 {published data only}
Downs RW Jr, Bell NH, Ettinger MP, Walsh BW, Favus MJ,
Mako B, et al.Comparison of alendronate and intranasal
calcitonin for treatment of osteoporosis in postmenopausal
women. Journal of Clinical Endocrinology & Metabolism
2000;85(5):1783–8.
Evio 2004 {published data only}
Evio S, Tiitinen A, Laitinen K, Ylikorkala O, Valimaki MJ.
Effects of alendronate and hormone replacement therapy,
alone and in combination, on bone mass and markers of
bone turnover in elderly women with osteoporosis. Journal
of Clinical Endocrinology & Metabolism 2004;89(2):626–31.
Gonnelli 2002 {published data only}
Gonnelli S, Cepollaro C, Montagnani A, Martini S,
Gennari L, Mangeri M, et al.Heel ultrasonography in
monitoring alendronate therapy: a four-year longitudinal
study. Osteoporosis International 2002;13(5):415–21.
Greenspan 2002a {published data only}
Greenspan SL, Emkey RD, Bone HG, Weiss SR, Bell
NH, Downs RW, et al.Significant differential effects of
alendronate, estrogen or combination therapy on the
rate of bone loss after discontinuation of treatment of
postmenopausal osteoporosis. A randomized, double-blind,
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Greenspan 2002b {published data only}
Greenspan SL, Schneider DL, McClung MR, Miller
PD, Schnitzer TJ, Bonin R, et al.Alendronate improves
bone mineral density in elderly women with osteoporosis
residing in long-term care facilities. A randomized, double-
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Greenspan 2003 {published data only}
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Harris 1993 {published data only}
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Ventura JN, et al.The effect of short term treatment with
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37Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
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SE ONLY
Heijckmann 2002 {published data only}
Heijckmann AC, Juttmann JR, Wolffenbuttel BH.
Intravenous pamidronate compared with oral alendronate
for the treatment of postmenopausal osteoporosis. [see
comment]. Netherlands Journal of Medicine 2002;60(8):
315–9.
Ho 2005 {published data only}
Ho AY, Kung AW, Ho AYY, Kung AWC. Efficacy
and tolerability of alendronate once weekly in Asian
postmenopausal osteoporotic women. Annals of
Pharmacotherapy 2005;39(9):1428–33. [MEDLINE: 109]
Hochberg 1999 {published data only}
Hochberg MC, Ross PD, Black D, Cummings SR, Genant
HK, Nevitt MC, et al.Larger increases in bone mineral
density during alendronate therapy are associated with
a lower risk of new vertebral fractures in women with
postmenopausal osteoporosis. Fracture Intervention Trial
Research Group. Arthritis & Rheumatism 1999;42(6):
1246–54.
Hosking 2003 {published data only}
Hosking D, Adami S, Felsenberg D, Andia JC, Valimaki
M, Benhamou L, et al.Comparison of change in bone
resorption and bone mineral density with once-weekly
alendronate and daily risedronate: a randomised, placebo-
controlled study. Current Medical Research & Opinion 2003;
19(5):383–94.
Iwamoto 2004 {published data only}
Iwamoto J, Takeda T, Sato Y, Uzawa M. Determinants
of one-year response of lumbar bone mineral density to
alendronate treatment in elderly Japanese women with
osteoporosis. Yonsei Medical Journal 2004;45(4):676–82.
Johnell 2002 {published data only}
Johnell O, Scheele WH, Lu Y, Reginster JY, Need AG,
Seeman E. Additive effects of raloxifene and alendronate on
bone density and biochemical markers of bone remodeling
in postmenopausal women with osteoporosis. [see
comment]. Journal of Clinical Endocrinology & Metabolism
2002;87(3):985–92.
Kung 2000 {published data only}
Kung AW, Yeung SS, Chu LW. The efficacy and tolerability
of alendronate in postmenopausal osteoporotic Chinese
women: a randomized placebo-controlled study. Calcified
Tissue International 2000;67(4):286–90.
Kushida 2004 {published data only}
Kushida K, Shiraki M, Nakamura T, Kishimoto H, Morii
H, Yamamoto K, et al.Alendronate reduced vertebral
fracture risk in postmenopausal Japanese women with
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Lau 2000 {published data only}
Lau EM, Woo J, Chan YH, Griffith J. Alendronate prevents
bone loss in Chinese women with osteoporosis. Bone 2000;
27(5):677–80.
Luckey 2004 {published data only}
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S. Calcitriol and alendronate combination treatment in
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38Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Stepan 1999 {published data only}
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39Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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41Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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and secondary prevention of osteoporotic fractures in
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42Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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C H A R A C T E R I S T I C S O F S T U D I E S
Characteristics of included studies [ordered by study ID]
Ascott Evans 2003
Methods Randomized controlled trial
Primary prevention
Duration: 1 year
Blinding: double blind matching placebo, all study personnel blinded
Withdrawals:
Alendronate: 12/95 (12.6%)
Placebo: 13/49 (26.5%)
Total: 25/144 (17.4%)
Participants Source: 18 centres in 9 countries.
Inclusion Criteria: Women under 80 yrs old who had been postmenopausal for at least 3
years. Previous HRT for at least 1 yr which had been discontinued at least 3 months prior
to study. Low bone density between -3.5 and -1.5 of young normal
Exclusion Criteria: History of osteoporotic fracture or metabolic bone disease. Recent
bisphosphonate or other treatment known to affect bone metabolism
Treatment N = 95
Control N = 49
Age: 67.3 (6.6); YSM: 11.5 (7.3)
Calcium: not reported
BMD: not reported
T-score: -2.27 (0.65)
Vertebral Fractures: 0%
Interventions Alendronate 10 mg x 1 year vs placebo
(Calcium 500mg/day)
Outcomes Vertebral, Non Vertebral, Hip and Wrist Fractures: Adverse experiences were recorded
by blinded study personnel at each visit using non leading questions. No fractures were
reported
Notes
Risk of bias
Bias Authors’ judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
43Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Black 1996
Methods Randomized controlled trial
Secondary prevention
Blinding: double blind identical placebo, blinded radiologist
Duration: 3 years
Withdrawals:
Alendronate (available radiographs): 44 (4.2%)
Placebo (available radiographs): 37/1005 (3.7%)
Total (available radiographs): 81/2027 (4.0%)
Total (lost to follow up at close out): 78/2027 (3.8%)
Participants Source: Population-based listings in 11 metropolitan areas of the USA. Fracture Interven-
tion Trial
Inclusion Criteria: Age 55-81, postmenopausal for at least 2 years, femoral neck BMD 0.68
g/cm² Hologic
(2.1 SD below peak bone mass) or less.
Exclusion Criteria: Peptic ulcer disease (single hospital admission for upper GI bleeding
or 2 or more documented ulcers in previous 5 years), dyspepsia requiring daily treatment,
abnormal renal function, major medical problems, severe malabsorption, uncontrolled hy-
pertension, MI in previous 6 months, unstable angina, thyroid or parathyroid dysfunction,
estrogen or calcitonin in previous 6 months, bisphosphonates or fluorides at any time
Treatment N = 1022
Control N = 1005
Age: 71.0 (5.6); YSM: not reported
Calcium: 636 (407) mg/day
BMD (hip): 0.57 g/cm 2 (0.07)
T-score (hip): -3.3
Vertebral Fractures : 100%
Interventions Alendronate 5 mg x 2 years then 10 mg x 1 year vs placebo
(If intake < 1000 mg then received 500 mg Ca and 250 IU Vitamin D)
Outcomes Morphometric Vertebral Fractures:
Lateral radiographs were taken at baseline 24 and 36 months intervals. Morphometry was
performed with a translucent digitizer and cursor marking anterior, posterior and middle
heights for each vertebra. Baseline fractures were defined a height of > 3 SD below the mean
population level for that vertebrae. Incident fractures were defined as a decrease of 20%
and at least 4 mm from baseline. Any questionable fractures were reviewed by the study
radiologist. Technicians and radiologist were all blinded
Clinical Vertebral Fractures: Fractures that came to medical attention and were reported
by participants. Copy of radiograph was obtained and compared with baseline study ra-
diograph. Incident clinical fracture was defined by a semiquantitative reading by the study
radiologist
Non Vertebral, Hip and Wrist Fractures: Clinical fractures were initially reported by par-
ticipants and confirmed by a written radiological report. Excluded pathological fractures
e.g. malignancies, excessive trauma, face and skull
Notes
Risk of bias
44Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Black 1996 (Continued)
Bias Authors’ judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Bone 1997
Methods Randomized controlled trial
Secondary prevention
Blinding: double blind
Duration: 2 years
Withdrawals:
Total (for BMD analysis):
131/359 (36.5%)
Participants Source: 15 clinical sites in USA. Subjects stratified so that 2/3 would be age 70-85
Inclusion Criteria: Women age 60-85 in good health apart from osteoporosis. Lumbar
spine < -2.00 SD of peak bone mass (BMD 0.824g/cm² or less by Hologic DXA or 9.44
g/cm² or less by Lunar DXA)
Exclusion Criteria: More than 1 spinal crush fracture or spinal anatomy otherwise unsuitable
for DXA, history of recent major GI disease - peptic ulcer, esophageal ulcer, malabsorption,
use of drug to inhibit gastric acid secretion for > 2 wks, chronic NSAID therapy, agents
known to affect bone metabolism, unstable dose thyroid hormone replacement, uncorrected
vitamin D deficiency.
Treatment N = 86, 89, 93
Control N = 91
Age: 70.4 (5.6); YSM: 24.2 (9.9)
Calcium: 891(629) mg/day
BMD: 0.71 g/cm 2 (0.08)
T-score: -3.1
Vertebral Fractures: 37.4%
Interventions Alendronate 1, 2.5, or 5 mg placebo.
(500 mg calcium/day)
Outcomes Vertebral Fractures: Lateral thoracic and lumbar radiographs obtained at baseline and an-
nual visits were sent to a central evaluation facility where they were evaluated by a single
radiologist. Prevalent and incident fractures were scored using a semiquantitative scale as
being intact (unfractured or questionably fractured), or fractured (mild - 20 to 25% height
loss; moderate - 25-40% or severe - >40%)
Non-vertebral Fractures: Reported at each centre based on clinical presentation and con-
firmatory radiographs
Notes
Risk of bias
Bias Authors’ judgement Support for judgement
45Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
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Bone 1997 (Continued)
Allocation concealment (selection bias) Low risk A - Adequate
Chestnut 1995
Methods Randomized controlled trial
Secondary prevention
Blinding: double blind unspecified
Duration: 2 years
Withdrawals:
Total: 34/188 (18%)
Loss to follow up: 34/188 (18.09%)
Participants Source: Recruited by advertisements and medical announcements through seven centres in
the USA
Inclusion Criteria: Healthy women age 42 to 75 who were at least 5 years postmenopausal.
BMD = 2 SD below young normal (0.88g/cm²)
Exclusion Criteria: Presence of spine or hip fractures attributable to osteoporosis. Any
disease or drug therapy potentially affecting bone metabolism
Treatment N = 32, 30, 32, 32
Control N = 31
Age: 63.04 (6.27); YSM: 15.6 (7.3)
Calcium: 853 (516) mg/day
BMD: 0.75 g/cm 2 (0.09)
T-score: -2.7
Vertebral Fractures : 0%
Interventions Alendronate 5mg/day, or 10 mg/day, for 2 years 20 mg/day or 40 mg/day for 1 year followed
by 1 year of placebo or 40 mg for 3 months followed by 2.5 mg for 21 months vs placebo
for 2 years
(500 mg calcium/day)
Outcomes Vertebral Fractures: Lateral thoracic and lumbar radiographs were evaluated at each centre
for presence of prevalent and incident fractures at baseline and completion of treatment
Non-vertebral Fractures: Ascertainment not specified but patients were questioned about
intercurrent health problems at each visit. This outcome was not included in the meta-
analysis as non vertebral fractures weren’t broken down by study group
Notes
Risk of bias
Bias Authors’ judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
46Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
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Cummings 1998
Methods Randomized controlled trial
Primary prevention
Blinding: double blind, collection and review of data was blinded
Study duration: 4 years
Withdrawals:
Total (lost to follow at close out)
160/4432 (3.6 %)
Participants Source: Recruited principally though mass mailings from 11 community-based clinical
research centres in the USA. Fracture Intervention Trial
Inclusion Criteria: Age 55-80, postmenopausal for at least 2 years, femoral neck BMD 0.68
g/cm² or less Hologic. At the time of study this was thought to correspond to -2 SD below
peak mass but subsequently found to correspond to a t-score of -1.6 based on the Third
National Health and Nutritional Examination Survey. Consequently 1/3 of participants
had higher BMD than expected
Exclusion Criteria: Vertebral fractures, Peptic ulcer disease (single hospital admission for
upper GI bleeding or 2 or more documented ulcers in previous 5 years), dyspepsia requiring
daily treatment, abnormal renal function, major medical problems, severe malabsorption,
uncontrolled hypertension, MI in previous 6 mos, unstable angina, thyroid or parathyroid
dysfunction, estrogen or calcitonin in previous 6 mos, bisphosphonates or fluorides at any
time
Treatment N = 2214
Control N = 2218
Age : 67.6 (6.1); YSM: not reported
Calcium: 636 (400) mg/day
BMD: 0.84 g/cm2 (0.13)
T-score: -1.9
Vertebral Fractures : 0%
Interventions Alendronate 5 mg for 2 yrs then increased to 10 mg for 2 years vs placebo
(If intake < 1000 mg then received 500 mg Ca and 250 IU Vitamin D)
Outcomes Vertebral Morphometric Fractures: Lateral spine radiographs were obtained at baseline and
4 years. An incident fracture was defined as a decrease of 20% and 4 mm or more in any
vertebral height which was confirmed by repeat measurement. All assessments were blinded
Clinical Fractures: Defined as a fractured diagnosed by a physician. Self reports were con-
firmed by written reports of radiographs or other tests. Excluded pathologic fractures,
trauma sufficient to fracture a young adult bone, facial and skull fractures
Notes
Risk of bias
Bias Authors’ judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
47Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
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Durson 2001
Methods Randomized controlled trial
Secondary prevention
Blinding: no blinding reported
Duration: 1 year
Withdrawals:
Alendronate: 13/51 (25.5%)
Control: 15/50 (30.0%)
Total: 28/101 (28%)
Participants Source: Postmenopausal women applying to one centre’s department of physical medicine
and rehabilitation in Turkey
Inclusion Criteria: BMD of 2 SD or more below young adult mean at either lumbar spine
or femoral neck
Exclusion Criteria: Drug or alcohol abuse, bone metabolism disorder, active GI or liver
disease, renal failure or calculi, treatment with specific therapy for osteoporosis, corticos-
teroids, malignancy, disorder of calcium metabolism, lumbar vertebrae abnormalities pre-
venting evaluation of BMD.
Treatment N = 51
Control N = 50
Age: 61 (7.8); YSM: 15.59 (8.04)
Calcium: not reported
BMD: 0.84 g/cm (0.08)
T-score: -1.9
Vertebral Fractures: not reported
Interventions Alendronate 10 mg/day plus calcium 1000 mg/day x 1 yr vs calcium 1000 mg
Outcomes Vertebral Fractures: Lateral and anteroposterior X-rays of thoracic and lumbar vertebrae
were performed at baseline, 6 months and 12 months. A new vertebral fracture was defined
as a decrease of 20% and at least 4 mm of height in any vertebrae
Notes
Risk of bias
Bias Authors’ judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
48Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
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Greenspan 1998
Methods Randomized controlled trial
Secondary prevention
Blinding: double blind, matching placebo
Study duration: 2.5 years
Loss to follow up: Alendronate:14/60 (23.3%)
Placebo:15/60 (25.0%)
Total: 29/120 (24.2%)
Participants Source: Unselected women from one city (Boston) in the USA were recruited by advertise-
ment
Inclusion Criteria: Healthy ambulatory community dwelling age 65 or older. Criteria not
based on BMD
Exclusion Criteria: History of any illness affecting bone and mineral metabolism - (renal,
malignancy, hyperthyroidism, hyperparathyroidism, malabsorption), medications affecting
bone metabolism, treatment for osteoporosis (bisphosphonates, HRT, calcitonin) within 1
year.
Treatment N = 60
Control N = 60
Age: 70 (4.6); YSM: not reported
Calcium: 719 (465) mg/day
BMD: 0.57 g/cm2 (0.11)
T-score: -4.3
Vertebral Fractures: not reported
Interventions Alendronate 5 mg for year 1, 10 mg for year 2 vs placebo,
(if Ca intake < 1000 mg - 250 mg Ca and/or 125 IU vitamin D/day)
Outcomes Non-vertebral Hip and Wrist: Ascertainment not described.
Notes
Risk of bias
Bias Authors’ judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Greenspan 2002
Methods Randomized controlled trial
Secondary prevention
Blinding: double blind matching placebo
Duration: 2 years
Withdrawals:
Not reported
Participants Source: Female residents in long term care facilities in 25 centre in USA
Inclusion Criteria: Ambulatory, age 65 or older with BMD T-score of -2 or less at lumbar
49Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
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Greenspan 2002 (Continued)
spine or hip.
Exclusion Criteria: Disorders of bone mineralization, 25-hydroxycholecalciferol < 25 nmol/
L, untreated hyperthyroidism, recent major upper GI mucosal erosive disease, or use of
bone active agents
Treatment N = 163
Control N = 164
Age: 78.5 (range 65-91); YSM: not reported
Calcium: not reported
BMD: not reported
T-score: (mean range hip and spine) -3.5 to-2.4
Fractures: (history of any) 55%
Interventions Alendronate 10 mg/day x 2yrs vs placebo
(Vitamin D 400 IU/day and if dietary calcium was < 1500 mg/day they received calcium
500mg/day.)
Outcomes Hip Fractures: Ascertainment not reported.
Notes
Risk of bias
Bias Authors’ judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Hosking 1998
Methods Randomized controlled trial
Primary prevention
Blinding: double blind, blinded BMD measurement and analysis
Duration: 2 years
Withdrawals: Alendronate:2.5mg 92/499 (18.4%)
Alendronate 5mg: 102/498 (20.5%)
Placebo: 93/502 (18.5%)
Total: 287/1499 (19.1%)
Withdrawals
Participants Source: Recruited by direct mailing, advertisements or telephone. Multicentre - USA, UK
and Denmark
Inclusion Criteria: Postmenopausal at least 6 months (confirmed by FSH) and in good
health. Only 10% of women at each centre were allowed to have a lumbar-spine BMD
below 0.8 g/square metre
(DEXA).
Exclusion Criteria: Abnormal renal function, cancer, peptic ulcer or esophageal disease
requiring prescription medication within the previous five years, previous treatment with
bisphosphonate or fluoride, therapy with phosphate-binding antacid, HRT within previous
3 months, therapy with any drug which affects the skeleton.
50Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
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Hosking 1998 (Continued)
Treatment N = 499, 498
Control N = 502
Age: 53 (4); YSM: 6 (5)
Calcium: 923 (505) mg/day
BMD: 0.94 g/cm 2 (0.12)
T-score: -1.0
Vertebral Fractures: NR
Interventions Alendronate 2.5 or 5mg vs placebo
(< 500mg calcium intake encouraged to increase)
Outcomes Vertebral and Non-Vertebral Fractures:
Women were questioned about any symptoms at clinic visits every 3 months. All un-
favourable clinical effects including fractures were evaluated with respect to severity, dura-
tion, seriousness, relation to study drug and outcome
Notes
Risk of bias
Bias Authors’ judgement Support for judgement
Allocation concealment (selection bias) Low risk A - Adequate
Liberman 1995
Methods Randomized controlled trial
Secondary prevention
Blinding: double blind, blinded radiologists
Withdrawals:
Alendronate: 97/597 (16.2%)
Placebo: 65/397 (16.5%)
Total: 162/994 (16.3 %)
Duration: 3 years
Participants Source: Two multicentre studies, one in the US, and the other in Australia, Canada, Europe,
Israel, Mexico, New Zealand, South America
Inclusion Criteria: Postmenopausal (= 5 yrs) women age 45-80 with lumbar BMD at least
2.5 SD below premenopausal mean
Exclusion Criteria: Other causes for osteoporosis (glucocorticoids, vitamin D deficiency,
Pagets, hyperparathyroidism), active peptic ulcer disease, abnormal renal or hepatic func-
tion, abnormalities of spine precluding assessment of BMD for 3 lumbar vertebrae, history
or hip fracture, prior bisphosphonates, HRT, calcitonin, fluoride, or anabolic steroid in
previous 12 months.
Treatment N = 597
Control N = 397
Age:64 (7); YSM: 16.5
Calcium: 739 (537) mg/day
51Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
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Liberman 1995 (Continued)
BMD: 0.71
T-score: -3.1
Vertebral Fractures: 21%
Interventions Alendronate 5, 10 or 20/5 mg vs placebo
(500 mg calcium/day)
Outcomes Vertebral fractures, vertebral deformities and height loss. (Deformities and height loss not
included in this review.)
Vertebral Fractures: Lateral thoracic and lumbar spine films were obtained at baseline, one,
two, and three years. Standard values for target-to-film distance and centering were used at
each centre. Vertebral heights were determined at a radiology centre by observers blinded
to both treatment and sequence. All films from each woman were digitized at the same time
and anterior, middle and posterior vertebral heights were calculated with using computer
software. Prevalent fractures were determined by comparing baseline vertebral height ratios
to a reference group. A ratio of > -3 SD was considered a fracture. Incident fractures were
defined as a reduction of at least 20% and 4 mm between baseline and follow up
Non-Vertebral Fractures, Hip and Wrist: All reported symptomatic fractures were recorded
with no attempt to exclude fractures on the basis of degree of trauma
Notes
Risk of bias
Bias Authors’ judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Pols 1999
Methods Randomized controlled trial
Secondary prevention
Blinding: double blind matching placebo
Duration: 1 year
Withdrawals:
Alendronate: 118/950 (12.4%)
Control: 93/958 (9.7%)
Total: 211/1908 (11.1 %)
Participants Source: 153 centres in 34 countries in Europe, Latin America, Australia, Canada, South
Africa and China.
.
Inclusion Criteria: Postmenopausal for at least 3 years, not older than age 85, lumbar BMD
(L2-4) at least 2 SD below the premenopausal mean (=0.86 g/cm² (DXA) or =0.98 g/cm²
(Hologic)). At lease 3 vertebrae from L1-L4 had to be evaluable by DXA to determine
BMD. In good health and between 20% below and 50% above ideal body weight
Exclusion Criteria: Other metabolic bone disease, disturbed parathyroid or thyroid, major
GI disease (peptic ulcer or malabsorption, drug to inhibit gastric > 2 week within past 3
52Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
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Pols 1999 (Continued)
mos), MI within 1 year, uncontrolled hypertension or angina, impaired renal function,
bisphosphonates or fluoride within 6 months, estrogen ipriflavone or calcitonin within
4 months, anabolic steroids, glucocorticoid or progestin within 6 months, medication
influencing bone metabolism - vitamin A > 10,000 IU/day, vitamin D > 1000 IU/day,
anticonvulsants, phosphate-binding antacids,
Treatment N = 950
Control N = 958
Age: 62.8 (7.4); YSM: 15.9 (1.5)
Calcium: Not available
BMD: 0.72 g/cm2 (0.08)
T-score: -2.97
Vertebral Fractures: not reported
Interventions Alendronate 10 mg, vs placebo
(500mg calcium/day)
Outcomes Non- Vertebral, Hip, Wrist: Clinical fractures were assessed through adverse event reporting.
Supporting documentation for each fracture i.e. radiographs and/or radiology reports,
hospital discharge reports with clinical diagnosis or confirmation by investigator/treating
physician
Notes
Risk of bias
Bias Authors’ judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
t-score calculated using the lumbar spine BMD [(LS BMD -1.047)/0.110];
YSM=Years Since Menopause;
BMD=Bone Mineral Density;
Txt=Treatment;
HRT=Hormone Replacement Therapy
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Adami 1993 Duplicate or earlier report of another study.
Adami 1995 Lack of appropriate fracture data (i.e. reported as adverse events or unspecified)
Aki 2003 Lack of fracture outcome.
53Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
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(Continued)
Bell 2002 Lack of appropriate fracture data (i.e. reported as adverse events or unspecified)
Bettembuk 1999 Duplicate or earlier report of another study.
Black 2000 Duplicate or earlier report of another study.
Black 2003 Lack of an appropriate control group.
Body 2002 Lack of an appropriate control group.
Boivin 2000 Lack of fracture outcome.
Bone 2000 Lack of appropriate fracture data (i.e. reported as adverse events or unspecified)
Bone 2004 Extension/discontinuation study.
Bonnick 1998 Lack of appropriate fracture data (i.e. reported as adverse events or unspecified)
Bouxsein 1999 Lack of fracture outcome.
Chailurkit 2003 Lack of fracture outcome.
Chailurkit 2004 Lack of an appropriate control group.
Chavassieux 1997 Lack of fracture outcome.
Cheng 2002 Duration of therapy < 1 year.
Chesnut 1993 Duration of therapy < 1 year.
Cummings 2000 Lack of fracture outcome.
Davas 2003 Lack of an appropriate control group.
Devogelaer 1996 Duplicate or earlier report of another study.
Dobnig 2006 Lack of fracture outcome.
Downs 2000 Lack of appropriate fracture data (i.e. reported as adverse events or unspecified)
Evio 2004 Lack of an appropriate control group.
Gonnelli 2002 Lack of fracture outcome.
Greenspan 2002a Extension/discontinuation study.
Greenspan 2002b Duration of therapy < 1 year.
54Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
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(Continued)
Greenspan 2003 Lack of appropriate fracture data (i.e. reported as adverse events or unspecified)
Harris 1993 Duration of therapy < 1 year.
Heijckmann 2002 Non randomized.
Ho 2005 Lack of fracture outcome.
Hochberg 1999 Duplicate or earlier report of another study.
Hosking 2003 Lack of appropriate fracture data (i.e. reported as adverse events or unspecified)
Iwamoto 2004 Lack of an appropriate control group.
Johnell 2002 Lack of fracture outcome.
Kung 2000 Lack of fracture outcome.
Kushida 2004 Lack of an appropriate control group.
Lau 2000 Lack of fracture outcome.
Luckey 2004 Lack of an appropriate control group.
Malavolta 1999 Duration of therapy < 1 year.
McClung 1998 Lack of fracture outcome.
McClung 2004 Extension study.
Murphy 2001 Lack of appropriate fracture data (i.e. reported as adverse events or unspecified)
Nenonen 2005 Lack of fracture outcome.
Palomba 2002 Lack of an appropriate control group.
Payer 2000 Duration of therapy < 1 year.
Ravn 1999a Lack of fracture outcome.
Ravn 1999b Lack of fracture outcome.
Ravn 1999c Extension/discontinuation study.
Ravn 2000 Extension/discontinuation study.
Rhee 2006 Lack of fracture outcome.
55Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
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(Continued)
Rittmaster 2000 Lack of an appropriate control group.
Rizzoli 2002 Lack of an appropriate control group.
Rossini 1994 Duration of therapy < 1 year.
Rossini 2000 Lack of fracture outcome.
Rozkydal 2003 Lack of an appropriate control group.
Sahota 2000 Lack of an appropriate control group.
Sambrook 2004a Lack of an appropriate control group.
Sambrook 2004b Extension/discontinuation study.
Sawka 2003 Non-randomized.
Schneider 1999 Lack of fracture outcome.
Schnitzer 2000 Lack of an appropriate control group.
Seeman 1999 Duplicate or earlier report of another study.
Simon 2002 Lack of an appropriate control group.
Sosa 2002 Lack of an appropriate control group.
Stepan 1999 Lack of fracture outcome.
Tiras 2000 Lack of an appropriate control group.
Tucci 1996 Duplicate or earlier report of another study.
Tutuncu 2005 Lack of fracture outcome.
Uusi-Rasi 2003 Lack of fracture outcome.
van der Poest 2000 Lack of fracture outcome.
Vasikaran 1995 Lack of an appropriate control group.
Yen 2000 Lack of fracture outcome.
Yildirim 2005 Lack of fracture outcome.
56Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
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D A T A A N D A N A L Y S E S
Comparison 1. Alendronate 10 mg vs Control - all years baseline denominators
Outcome or subgroup titleNo. of
studies
No. of
participants Statistical method Effect size
1 Vertebral Fractures 6 7361 Risk Ratio (M-H, Fixed, 95% CI) 0.55 [0.45, 0.67]
1.1 Vertebral primary 2 4576 Risk Ratio (M-H, Fixed, 95% CI) 0.55 [0.38, 0.80]
1.2 Vertebral secondary 4 2785 Risk Ratio (M-H, Fixed, 95% CI) 0.55 [0.43, 0.69]
Comparison 2. Alendronate 10 mg vs Control - all years baseline denominators
Outcome or subgroup titleNo. of
studies
No. of
participants Statistical method Effect size
1 Non Vertebral Fractures 6 9625 Risk Ratio (M-H, Fixed, 95% CI) 0.84 [0.74, 0.94]
1.1 Non-vertebral primary 2 4576 Risk Ratio (M-H, Fixed, 95% CI) 0.89 [0.76, 1.04]
1.2 Non vertebral secondary 4 5049 Risk Ratio (M-H, Fixed, 95% CI) 0.77 [0.64, 0.92]
Comparison 3. Alendronate 10 mg vs Control - all years baseline denominators
Outcome or subgroup titleNo. of
studies
No. of
participants Statistical method Effect size
1 Hip Fractures 7 9952 Risk Ratio (M-H, Fixed, 95% CI) 0.61 [0.40, 0.92]
1.1 Hip primary 2 4576 Risk Ratio (M-H, Fixed, 95% CI) 0.79 [0.44, 1.44]
1.2 Hip secondary 5 5376 Risk Ratio (M-H, Fixed, 95% CI) 0.47 [0.26, 0.85]
Comparison 4. Alendronate 10 mg vs Control - all years baseline denominators
Outcome or subgroup titleNo. of
studies
No. of
participants Statistical method Effect size
1 Wrist Fractures 6 9729 Risk Ratio (M-H, Fixed, 95% CI) 0.84 [0.66, 1.06]
1.1 Wrist primary 2 4576 Risk Ratio (M-H, Fixed, 95% CI) 1.19 [0.87, 1.62]
1.2 Wrist secondary 4 5153 Risk Ratio (M-H, Fixed, 95% CI) 0.52 [0.36, 0.75]
57Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
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Comparison 5. Alendronate 10 mg vs Control - 1 year baseline denominators
Outcome or subgroup titleNo. of
studies
No. of
participants Statistical method Effect size
1 Fractures 4 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
1.1 Vertebral 3 306 Risk Ratio (M-H, Fixed, 95% CI) 0.84 [0.43, 1.63]
1.2 Nonvertebral fractures 2 2052 Risk Ratio (M-H, Fixed, 95% CI) 0.52 [0.30, 0.89]
1.3 Hip fractures 2 2052 Risk Ratio (M-H, Fixed, 95% CI) 0.67 [0.11, 4.01]
1.4 Wrist fractures 2 2052 Risk Ratio (M-H, Fixed, 95% CI) 0.40 [0.16, 1.04]
Comparison 6. Alendronate 10 mg vs Control - 1 year baseline denominators
Outcome or subgroup titleNo. of
studies
No. of
participants Statistical method Effect size
1 Fractures 4 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
1.1 Vertebral primary 1 144 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
1.2 Vertebral secondary 2 162 Risk Ratio (M-H, Fixed, 95% CI) 0.84 [0.43, 1.63]
1.3 Nonvertebral primary 1 144 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
1.4 Non vertebral secondary 1 1908 Risk Ratio (M-H, Fixed, 95% CI) 0.52 [0.30, 0.89]
1.5 Hip primary 1 144 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
1.6 Hip secondary 1 1908 Risk Ratio (M-H, Fixed, 95% CI) 0.67 [0.11, 4.01]
1.7 Wrist primary 1 144 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
1.8 Wrist secondary 1 1908 Risk Ratio (M-H, Fixed, 95% CI) 0.40 [0.16, 1.04]
Comparison 7. Alendronate 10 mg vs Control - 2 years baseline denominators
Outcome or subgroup titleNo. of
studies
No. of
participants Statistical method Effect size
1 Fractures 2 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
1.1 Vertebral secondary 1 61 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
1.2 Hip secondary 1 327 Risk Ratio (M-H, Fixed, 95% CI) 0.50 [0.09, 2.71]
58Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
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Comparison 8. Alendronate 10 mg vs Control - 3 years baseline denominators
Outcome or subgroup titleNo. of
studies
No. of
participants Statistical method Effect size
1 Fractures 3 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
1.1 Vertebral secondary 2 2623 Risk Ratio (M-H, Fixed, 95% CI) 0.52 [0.41, 0.67]
1.2 Nonvertebral secondary 3 3141 Risk Ratio (M-H, Fixed, 95% CI) 0.82 [0.67, 0.99]
1.3 Hip secondary 3 3141 Risk Ratio (M-H, Fixed, 95% CI) 0.45 [0.23, 0.87]
1.4 Wrist secondary 3 3245 Risk Ratio (M-H, Fixed, 95% CI) 0.55 [0.37, 0.82]
Comparison 9. Alendronate 10 mg vs Control - 4 years baseline denominators
Outcome or subgroup titleNo. of
studies
No. of
participants Statistical method Effect size
1 Fractures 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
1.1 Vertebral primary 1 4432 Risk Ratio (M-H, Fixed, 95% CI) 0.55 [0.38, 0.80]
1.2 Nonvertebral primary 1 4432 Risk Ratio (M-H, Fixed, 95% CI) 0.89 [0.76, 1.04]
1.3 Hip primary 1 4432 Risk Ratio (M-H, Fixed, 95% CI) 0.79 [0.44, 1.44]
1.4 Wrist primary 1 4432 Risk Ratio (M-H, Fixed, 95% CI) 1.19 [0.87, 1.62]
Comparison 10. Alendronate 5 mg vs Control - all years baseline denominators
Outcome or subgroup titleNo. of
studies
No. of
participants Statistical method Effect size
1 Fractures 4 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
1.1 Vertebral secondary 3 2807 Risk Ratio (M-H, Fixed, 95% CI) 0.40 [0.29, 0.55]
1.2 Non vertebral primary 1 999 Risk Ratio (M-H, Fixed, 95% CI) 1.58 [0.82, 3.05]
1.3 Non vertebral secondary 1 184 Risk Ratio (M-H, Fixed, 95% CI) 0.55 [0.26, 1.18]
Comparison 11. Alendronate 10 mg vs Control - all years baseline denominators
Outcome or subgroup titleNo. of
studies
No. of
participants Statistical method Effect size
1 Withdrawals due to side effects 6 8796 Risk Ratio (M-H, Fixed, 95% CI) 0.95 [0.83, 1.09]
2 Withdrawals overall 5 3273 Risk Ratio (M-H, Fixed, 95% CI) 1.10 [0.94, 1.29]
59Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
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A D D I T I O N A L T A B L E S
Table 1. Clinical Relevance Table for Fracture - Primary Prevention Trials
Outcome # Patients #
Trials
Control
Event Rate
Wt Absolute
RD
Wt Rel %
Change
NNT B Statistical Sig Quality of
Evidence
Verte-
bral Fractures
(Trial Popula-
tions)
- Primary Pre-
vention (alen-
dronate
10 mg/day for
1-4 yrs)
4,576 (2) 3.4% (3 out of
100)
-2% 2 fewer
patients out of
100
-45% (I) 66 Statistically
significant
Gold
95% confi-
dence interval
(-2, -1) (-62, -20) (48, 148)
Verte-
bral Fractures
(Low
Risk Woman)
- Primary Pre-
vention (alen-
dronate
10 mg/day for
1-4 yrs)
4,576 (2) 1.2 % (1 out of
100)
Not applicable -45% (I) 186 Statistically
significant
Gold
95% confi-
dence interval
(-62, -20) (135, 417)
Verte-
bral Fractures
(Moderate
Risk Woman)
- Primary Pre-
vention (alen-
dronate
10 mg/day for
1-4 yrs)
4,576 (2) 5.3 % (5 out of
100)
Not applicable -45% (I) 42 Statistically
significant
Gold
95% confi-
dence interval
(-62, -20) (31, 95)
Non Vertebral
Fractures
(Trial Popula-
tions)
- Primary Pre-
vention (alen-
4,576 (2) 13.0%
(13 out of 100
patients)
-1% 1 fewer
patient out of
100
-11% (I) Not applicable Not statis-
tically signifi-
cant
Gold
60Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
INTERNAL U
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Table 1. Clinical Relevance Table for Fracture - Primary Prevention Trials (Continued)
dronate
10mg/day for
1-4 years)
95% confi-
dence interval
(-3, 0) (-24, 4)
Non Vertebral
Fractures
(Low
Risk Woman)
- Primary Pre-
vention (alen-
dronate
10mg/day for
1-4 years)
4,576 (2) 8.6% (9 out of
100)
Not applicable -11% (I) Not applicable Not statis-
tically signifi-
cant
Gold
95% confi-
dence interval
(-24, 4)
Non Vertebral
Fractures
(Moderate
Risk Woman)
- Primary Pre-
vention (alen-
dronate
10mg/day for
1-4 years)
4,576 (2) 16.5% (17 out
of 100)
Not applicable -11% (I) Not applicable Not statis-
tically signifi-
cant
Gold
95% confi-
dence interval
(-24, 4)
Hip Fractures
(Trial Popula-
tions)
- Primary Pre-
vention (alen-
dronate
10mg/day for
1-4 yrs
4,576 (2) 1.1% (1 out of
100)
0% fewer pa-
tients out of
100
-21% (I) Not applicable Not statis-
tically signifi-
cant
Gold
95% confi-
dence interval
(-1, 0) (-56, 44)
Hip Fractures
(Low
Risk Woman)
- Primary Pre-
vention (alen-
4,576 (2) 0.4% (0 out of
100)
Not applicable -21% (I) Not applicable Not statis-
tically signifi-
cant
Gold
61Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Table 1. Clinical Relevance Table for Fracture - Primary Prevention Trials (Continued)
dronate
10mg/day for
1-4 yrs
95% confi-
dence interval
(-56, 44)
Hip Fractures
(Moderate
Risk Woman)
- Primary Pre-
vention (alen-
dronate
10mg/day for
1-4 yrs
4,576 (2) 1.9% (2 out of
100)
Not applicable -21% (I) Not applicable Not statis-
tically signifi-
cant
Gold
95% confi-
dence interval
(-56, 44)
Wrist Frac-
tures (Trial
Populations)
- Primary Pre-
vention (alen-
dronate
10 mg/day for
1-4 yrs)
4,576 (2) 3.1% (3 out of
100)
1 1 more pa-
tient out of
100
19% (W) Not applicable Not statis-
tically signifi-
cant
Gold
95% confi-
dence interval
(0, 2) (-13, 38)
Wrist Frac-
tures (Low
Risk Woman)
- Primary Pre-
vention (alen-
dronate
10 mg/day for
1-4 yrs)
4,576 (2) Not available Not applicable 19% (W) Not applicable Not statis-
tically signifi-
cant
Gold
95% confi-
dence interval
(-13, 38)
Wrist Frac-
tures (Moder-
ate
Risk Woman)
- Primary Pre-
vention (alen-
dronate
4,576 (2) Not available Not applicable 19% (W) Not applicable Not statis-
tically signifi-
cant
Gold
62Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Table 1. Clinical Relevance Table for Fracture - Primary Prevention Trials (Continued)
10 mg/day for
1-4 yrs)
95% confi-
dence interval
(-13, 38)
Legend Pri-
mary preven-
tion = bone
density < 2
SD values be-
low peak bone
mass
and/or no his-
tory of verte-
bral compres-
sion fractures
For Trial Pop-
ulation rates
are based on
the event rate
in the control
group. Low
and Mod-
erate Risk, are
5 year com-
munity popu-
lation risks de-
rived from the
following vari-
ables from the
FRACTURE
Index: age,
fracture after
50 yrs., mater-
nal hip frac-
ture after 50
yrs., weight <
125 lbs, smok-
ing, using
arms to assist
standing and
BMD. Low =
FRACTURE
Index score 1-
2, Moderate =
FRAC-
TURE Index
score 5 (Black
2001) see Fig-
ure 1
Wt =
weighted, RD
= risk differ-
ence
Wt Rel
= weighted rel-
ative percent
change, I = im-
provement
NNT
B = number
needed to ben-
efit
Gold level: At
least one ran-
domised clini-
cal trial meets
all of the fol-
lowing criteria
for the major
outcome
(s) as reported:
Sample sizes of
at least 50 per
group. If a sta-
tistically
significant dif-
ference is not
found they
must be pow-
ered for 20%
relative differ-
ence in the rel-
evant out-
come. Blind-
ing of patients
and as-
sessors for out-
comes. Han-
dling of with-
drawals > 80%
follow up (im-
puta-
tions based on
methods such
as Last Obser-
vation Carried
For-
ward (LOCF)
acceptable).
Concealment
of treatment
63Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Table 1. Clinical Relevance Table for Fracture - Primary Prevention Trials (Continued)
allocation. Sil-
ver level: Ran-
domised trial
does not meet
the above cri-
teria
Table 2. Clinical Relevance Table for Fracture - Secondary Prevention Trials
Outcome # Patients #
Trials
Control
Event Rate
Wt Absolute
RD
Wt Rel %
Change
NNT B Statistical Sig Quality of
Evidence
Verte-
bral Fractures
(Trial popula-
tions) - Sec-
ondary Pre-
vention (alen-
dronate 10 mg
for 1-3 yrs)
2,785 (4) 12.2% (12 out
of 100)
-6% 6 fewer
patients out of
100
-45% (I) 19 Statistically
significant
Gold
95% confi-
dence interval
(-8, -4) (-57, -31) (15, 25)
Verte-
bral Fractures
(Moderate
Risk Woman)
- Secondary
Pre-
vention (alen-
dronate 10 mg
for 1-3 yrs)
2,785 (4) 5.3% (5 out of
100)
NA -45% (I) 42 Statistically
significant
Gold
95% confi-
dence interval
(-57, -31) (34, 61)
Verte-
bral Fractures
(High
Risk Woman)
- Secondary
Pre-
vention (alen-
dronate 10 mg
for 1-3 yrs)
2,785 (4) 11.2% (11 out
of 100)
NA -45% (I) 20 Statistically
significant
Gold
64Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Table 2. Clinical Relevance Table for Fracture - Secondary Prevention Trials (Continued)
95% confi-
dence interval
(-57, -31) (16, 29)
Non Vertebral
Fractures
(Trial Popula-
tion)- Sec-
ondary Pre-
vention (alen-
dronate
10mg/day for
1 - 3 yrs)
5049 (4) 9.3% (9 out of
100)
-2% 2 fewer
patients out of
100
-23% (I) 47 Statistically
significant
Gold
95% confi-
dence interval
(-4, -1) (-36, -8) (30, 135)
Non Vertebral
Fractures
(Moderate
Risk Woman)
- Secondary
Prevention
(alendronate
10mg/day for
1 - 3 yrs)
5049 (4) 16.5% (17 out
of 100)
NA -23% (I) 27 Statistically
significant
Gold
95% confi-
dence interval
(-36, -8) (17, 76)
Non Vertebral
Fractures
(High
Risk Woman)
- Secondary
Prevention
(alendronate
10mg/day for
1 - 3 yrs)
5049 (4) 27.5% (28 out
of 100)
NA -23% 16 Statistically
significant
Gold
95% confi-
dence interval
(-36, -8) (I) (11, 46)
Hip Fractures
(Trial Popula-
tion) - Sec-
ondary Pre-
vention (alen-
dronate
10mg/day for
5,376 (5) 1.3% ( out of
100)
-1% 1 fewer
patients out of
100
-53% ( -74, -
15) (I)
146 Statistically
significant
Gold
65Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Table 2. Clinical Relevance Table for Fracture - Secondary Prevention Trials (Continued)
1-3 yrs)
95% confi-
dence interval
(-1, 0) (104, 513)
Hip Fractures
(Moderate
Risk Woman)
- Secondary
Prevention
(alendronate
10mg/day for
1-3 yrs)
5,376 (5) 1.9% (2 out of
100)
NA -53% ( -74, -
15) (I)
100 Statistically
significant
Gold
95% confi-
dence interval
(72, 351)
Hip Fractures
(High
Risk Woman)
- Secondary
Prevention
(alendronate
10mg/day for
1-3 yrs)
5,376 (5) 8.9% (9 out of
100)
NA -53% ( -74, -
15) (I)
22 Statistically
significant
Gold
95% confi-
dence interval
(16, 75)
Wrist
Fractures
(Trial Popula-
tion) - Sec-
ondary Pre-
vention (alen-
dronate
10mg/day for
1-3 yrs)
5,153 (4) 2.9% (3 out of
100)
-1% 1 fewer
patients out of
100
-50% (-66, -
27) (I)
69 Statistically
significant
Gold
95% confi-
dence interval
(-2, -1) (53, 128)
Wrist Frac-
tures - Sec-
ondary Pre-
vention (alen-
dronate
10mg/day for
1-3 yrs)
5,153 (4) NA NA -50% (-66, -
27) (I)
NA Statistically
significant
Gold
66Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Table 2. Clinical Relevance Table for Fracture - Secondary Prevention Trials (Continued)
95% confi-
dence interval
Wrist Frac-
tures - Sec-
ondary Pre-
vention (alen-
dronate
10mg/day for
1-3 yrs)
5,153 (4) NA NA -50% (-66, -
27) (I)
NA Statistically
significant
Gold
Legend Secondary
prevention =
bone density
of at least 2
SD values be-
low peak bone
mass and/
or one or more
vertebral com-
pression frac-
tures
For Trial Pop-
ulation
rates are based
on the event
rate in the
control group.
Moderate and
High Risk, are
5 year com-
munity popu-
lation risks de-
rived from the
following vari-
ables
in the FRAC-
TURE Index:
age,
fracture after
50 yrs., mater-
nal hip frac-
ture after 50
yrs., weight <
125 lbs, smok-
ing, using
arms to assist
standing and
BMD. Mod-
erate = FRAC-
TURE Index
score 5, High
= FRAC-
TURE In-
dex score 8-13
(Black 2001)
see Figure 1
Wt =
weighted, RD
= risk differ-
ence
Wt Rel
= weighted rel-
ative percent
change, I = im-
provement
NNT
B = number
needed to ben-
efit
Gold level:
At
least one ran-
domised clini-
cal trial meets
all of the fol-
lowing criteria
for the major
outcome(s) as
reported:
Sample
sizes of at least
50 per group.
If a statistically
significant dif-
ference is not
found they
must be pow-
ered
for 20% rela-
tive difference
in the relevant
outcome.
Blind-
ing of patients
and assessors
for outcomes.
Han-
dling of with-
drawals > 80%
follow up (im-
puta-
tions based on
methods such
67Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Table 2. Clinical Relevance Table for Fracture - Secondary Prevention Trials (Continued)
as Last Obser-
vation Carried
For-
ward (LOCF)
acceptable).
Concealment
of treatment
allocation.
Silver level:
Ran-
domised trial
does not meet
the above cri-
teria.
F E E D B A C K
Feedback from Maryann Napoli, 2 June 2008
Summary
Date of Submission: 02-Jun-2008
Name: Maryann Napoli
Email Address: [email protected]
Personal Description: Occupation a consumer advocate
Feedback: I like the new format of the plain language summary, particularly the way you have expressed “best estimates.” But there is
a glaring omission: You should also provide an estimate of the number of hip fractures, vertebral fractures, etc out of 100 women who
do NOT take alendronate. If this and future PLS do not include numerical information about the no-treatment options, then it will
not be clear to readers what their chances of having a hip fracture, vertebral fracture, etc. are to begin with. People will want to know
“one fewer than what?”
Submitter agrees with default conflict of interest statement: I certify that I have no affiliations with or involvement in any organization
or entity with a financial interest in the subject matter of my feedback.
Reply
Thank you for your feedback about the Plain language summary. The CSMG has been and continues to be actively involved in research
to summarise our reviews in a format that is useful and comprehensible to consumers.
Your feedback addresses the issues around providing absolute event rates and absolute differences to consumers, in particular for
dichotomous outcomes. In summaries that we have published in earlier reviews, review authors presented primarily absolute event
rates without differences. In this review, differences were provided, but event rates were not. Unfortunately we do not have high quality
evidence to determine the best presentation, but we continue to investigate and explore the options. User testing of a variety of Plain
language summary formats, which is funded by the Cochrane Collaboration Opportunity Fund, is pending and we look forward to
the results.
As you have suggested, we have edited this Plain language summary to present absolute event rates.
68Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Contributors
George A. Wells, Nancy Santesso, Tamara Rader.
Feedback from Mark Porcheret, 22 December 2010
Summary
Date of Submission: 22-Dec-2010
Name: Mark Porcheret
Email Address: [email protected]
Personal Description: Occupation GP Research fellow
Feedback: In figure 6 on page 20 the “corresponding risk” for the outcome “hip fractures” for the moderate risk population is stated to
be 19 per 1000 (CI 5 to 16). Could you confimr this is a typo and should be 9 per 1000.
Also, I am trying to interpret this data for an EBP group I facilitate and have a question: the risks in figure 6 are 5yr risks comparing
people on alendronate to those not taking it. But the heading states it is for alendronate for 1-3yrs. So, I am not sure how to phrase the
evidence for use in the consultation. Does that data mean, for example for vertebral factures in the moderate risk populations, that:
“If you take a 1000 people like you, those at moderate risk, in 5yrs time 63 will have had a vertebral fracture, but if all 1000 took
alendronate for the 5 years only 29 will have had a vertebral fracture.” This is how such a comparison would normally be comminicated
with the period of risk / benefit being the same as the period of treatment, but the figure presents 5yr risks for 1-3yrs of treatment,
which complicates the message. Your views on this would be welcome before the meeting we have to discuss this on 12th January 2011.
Many thanks Mark Porcheret
Submitter agrees with default conflict of interest statement:
I certify that I have no affiliations with or involvement in any organization or entity with a financial interest in the subject matter of
my feedback.
Reply
Many thanks for your feedback on this review. Please find below our response to your comment after consultation with the lead author,
George Wells.
Regarding your first point, yes, we can confirm that there is a typo here and it should state 9 per 1000. We will fix this for the next
issue of the Library.
For your second point, yes, the risks in the table are for 5 year risks and your interpretation is correct (though the ’63’ in your email
should be ’53’ as from the table). The ’1-3’ years in the heading simply indicates that the relative risk came from studies of 1 to 3 years
duration (since this is the best evidence that we have) but were modeled on a 5-year time horizon. We agree this heading is confusing
so we will take the ’1-3’ out of the heading and explain this in a footnote in the table for the next issue. We also noticed that the high-
risk population should state 62/1000 instead of 62/100.
Thanks again for bringing this to our attention.
Contributors
George A Wells, Lara Maxwell.
69Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Feedback from Aaron M Tejani, 17 December 2010
Summary
Date of Submission: 17-Dec-2010
Name: Aaron M Tejani
Email Address: [email protected] Personal Description: Occupation a pharmacist
Feedback: In the review, alendronate was found to have a statistically significant benefit for primary vertebral fracture prevention (45%
RRR, 95% CI of 0.38 to 0.80). The results were compiled from two studies that were conducted by Ascott-Evans et al. (2) (2003) and
Cummings et al. (3) (1998) (as shown by Analysis 1.1 figure). Based on closer inspection of these two studies we have some specific
concerns.
The review (1) cited that vertebral fractures did not occur in neither the treatment nor control group in the study by Ascott-Evans et
al. (2) as shown in the Analysis 1.1 figure. However, the study did not report the incidence of vertebral fractures. It is incorrect to
assume that no vertebral fractures occurred simply because they were not reported in the trial publication. The authors of the review
need to clarify if unpublished vertebral fracture information was received from Ascott-Evans et al.
The other study that contributed to the vertebral fracture meta-analysis for alendronate was Cummings et al. 2003 (3). In this trial
vertebral fractures were solely radiographically determined and not clinical fractures. The review authors should emphasize that the
data used in the meta-analysis of alendronate in primary prevention from Cummings et al. 2003 was only for non-clinical vertebral
fractures.
If this review is revised, we urge the authors to also clarify whether alendronate reduces the risk of clinical vertebral fractures in
secondary prevention. It would be very useful if these authors also clarify the non-clinical versus clinical fracture issue for all the oral
bisphosphonate reviews.(4,5)
1. Wells GA, Crannery A, Peterson J, Boucher M, Shea B, Welch V, Coyle D, Tugwell P. Alendronate for the primary and secondary
prevention of osteoporotic fractures in postmenopausal women. Cochrane Database of Systematic Reviews 2008, Issue 1. Art. No.:
CD001155. DOI: 10.1002/14651858.CD001155.pub2.
2. Ascott-Evans BH, Guanabens N, Kivinen S, Stuckey BG, Magaril CH, Vandormael K, et al. Alendronate prevents loss of bone
density associated with discontinuation of homrone replacement therapy: a randomized controlled trial. Archives of Internal Medicine
2003; 163(7): 789-94.
3. Cummings SR, Black DM, Thompson DE, Appleggate WB, Barrett-Connor E, Musliner TA, et al. Effect of alendronate on risk
of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial. JAMA 1998;
280(24):2077-82.
4. Wells GA, Cranney A, Peterson J, Boucher M, Shea B, Welch V, Coyle D, Tugwell P. Etidronate for the primary and secondary
prevention of osteoporotic fractures in postmenopausal women. Cochrane Database of Systematic Reviews 2008, Issue 1. Art. No.:
CD003376. DOI: 10.1002/14651858.CD003376.pub3.
5. Wells GA, Cranney A, Peterson J, Boucher M, Shea B, Welch V, Coyle D, Tugwell P. Risedronate for the primary and secondary
prevention of osteoporotic fractures in postmenopausal women. Cochrane Database of Systematic Reviews 2008, Issue 1. Art. No.:
CD004523. DOI: 10.1002/14651858.CD004523.pub3.
Submitter agrees with default conflict of interest statement:
I certify that I have no affiliations with or involvement in any organization or entity with a financial interest in the subject matter of
my feedback.
70Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Reply
Dear Dr Tejani,
Thank you for your feedback regarding our review.
With respect to the Ascott-Evans study, we determined the absence of vertebral fractures from the information provided in the
publication. (We did not request additional data from any study authors as the selective response often elicited to such a request may
introduce a source of bias.) Fractures, in this paper, were assessed as adverse events. Adverse events were recorded by study personnel at
each visit using non-leading questions. In reporting these events, in the results section of the paper, the authors stated that “no fractures
were reported during the study”. We agree that it may have been presumptuous of us to assume the absence of vertebral fractures from
this report and we would not be adverse to removing this study from the analysis. Doing so, however, would not substantially alter our
results or conclusions.
Your concern regarding the Cummings paper is a point well taken. This was the only primary prevention study which reported both
radiographic and clinical fractures as separate outcomes. Since the other papers (with the exception of Ascott-Evans having 0 events)
reported only radiographic vertebral fractures we decided, for the sake of consistency, to use the radiographic outcome for Cummings
in the meta-analysis. (As well, all of the alendronate studies in the secondary prevention analysis reported only radiographic fractures.)
Your suggestion that we clarify the issue surrounding clinical and non clinical fractures for future bisphosphonate updates is a good
one and will be included in the next update of the review.
We hope that these responses are helpful. Please do not hesitate to contact us should you have any further questions or concerns.
Contributors
Geroge A. Wells, Elizabeth Ghogomu.
Feedback from George Hannah, 5 November 2010
Summary
Name: George hannah
Email Address: [email protected]
Personal Description: Occupation GP
Feedback: I am uncertain what length of treatment of alendronate is being referred to in the review, to produce the NNT. When you
may be treating women in their 60s to prevent fractures in their 80s? Does treatment have to be ongoing to produce the benefit? Is 5
years a standard length. How does this affect NNT? ie is the NNT in year one, less than year 2, year 3 etc of treatment.
Submitter has modified conflict of interest statement:
I certify that I have no affiliations with or involvement in any organization or entity with a financial interest in the subject matter of
my feedback.
Reply
Dear Dr Hannah,
The NNTs reported in our review are derived from the pooling of trials varying in length between 1 and 4 years. (The majority of
subjects stemmed from trials which had follow ups of 3 or 4 years). These studies were designed to evaluate the current use of alendronate
and did not provide for an off drug follow up period. The estimates reported in our review cannot be extrapolated to a future date at
which the patient is no longer taking the medication.
You had also asked if 5 years was a standard treatment length. We did not make any recommendations in the review regarding length
of treatment. We used 5 year risk estimates in our Summary of Findings tables and in Figure 9 as the FRACTURE Index (Black 2001)
used to classify women according to baseline risk factors was based on 5 year community population risks.
With respect to the effect of length of treatment on the NNTs, we did provide a breakdown of treatment effects by year of follow up
in Figure 11,which could, theoretically, be translated into NNTs. These estimates, however, should be viewed with caution as in some
cases they are comprised of interim time point data.
71Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Contributors
George A. Wells, Elizabeth Ghogomu.
W H A T ’ S N E W
Last assessed as up-to-date: 13 November 2007.
Date Event Description
8 July 2011 Feedback has been incorporated Responses to queries about:
1. clincal and non-clinical fractures
2. NNT calculation.
H I S T O R Y
Protocol first published: Issue 3, 2005
Review first published: Issue 1, 2008
Date Event Description
13 January 2011 Feedback has been incorporated Amendments in Figure 6: Summary of Findings for Secondary Prevention
12 August 2008 Feedback has been incorporated Absolute event rates included in the Plain language summary.
28 May 2008 Amended Converted to new review format.CMSG ID C004-R
C O N T R I B U T I O N S O F A U T H O R S
George Wells was involved in the conception, design and implementation of the project and contributed significantly to the writing of
the report.
Ann Cranney was involved with the conception of the review, data abstraction, analysis, interpretation and revision of the final report.
Joan Peterson screened the literature, was involved in the data abstraction, quality assessment and analysis of the primary trials and
contributed significantly to the writing of the report.
Michel Boucher assisted in the design of the analysis, reporting and interpretation of the findings and was involved in the writing of
the report.
Beverley Shea was involved in developing the protocol and conducting the systematic review.
Vivian Robinson was involved in developing the protocol and conducting the systematic review.
Douglas Coyle assisted with the design of the review and reviewed the analysis.
Peter Tugwell provided clinical rheumatology expertise and methodological guidance.
72Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
INTERNAL U
SE ONLY
D E C L A R A T I O N S O F I N T E R E S T
None.
S O U R C E S O F S U P P O R T
Internal sources
• Ottawa Hospital Research Institute, Canada.
External sources
• Canadian Agency for Drugs and Technologies in Health, Canada.
I N D E X T E R M S
Medical Subject Headings (MeSH)
Alendronate [∗therapeutic use]; Bone Density Conservation Agents [∗therapeutic use]; Fractures, Bone [∗prevention & control];
Fractures, Spontaneous [prevention & control]; Hip Fractures [prevention & control]; Osteoporosis, Postmenopausal [∗drug therapy];
Randomized Controlled Trials as Topic; Spinal Fractures [prevention & control]
MeSH check words
Female; Humans
73Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Risedronate for the primary and secondary prevention of
osteoporotic fractures in postmenopausal women (Review)
Wells GA, Cranney A, Peterson J, Boucher M, Shea B, Welch V, Coyle D, Tugwell P
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library2010, Issue 7
http://www.thecochranelibrary.com
Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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T A B L E O F C O N T E N T S
1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Figure 5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Figure 6. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
13RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 7. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Figure 8. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Figure 9. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Figure 10. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Figure 11. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
Figure 12. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
Figure 13. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
Figure 14. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
Figure 15. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Figure 16. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
Figure 17. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
Figure 18. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
Figure 19. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
Figure 20. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
Figure 21. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
Figure 22. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
31DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 23. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
34AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
35ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
35REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
39CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
49DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
52ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
60WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
60HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
60CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
61DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
61SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
61NOTES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
62INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
iRisedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
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[Intervention Review]
Risedronate for the primary and secondary prevention ofosteoporotic fractures in postmenopausal women
George A Wells1, Ann Cranney2, Joan Peterson3, Michel Boucher4, Beverley Shea5, Vivian Welch6, Doug Coyle7, Peter Tugwell8
1Cardiovascular Research Reference Centre, University of Ottawa Heart Institute, Ottawa, Canada. 2 Division of Rheumatology, Ottawa
Hospital, Ottawa, Canada. 3Clinical Epidemiology Unit, Ottawa Civic Hospital / Loeb Research Institute, Ottawa, Canada. 4HTA
Development Canadian Agency for Drugs and Technologies in Health (CADTH), Ottawa, Canada. 5Institute of Population Health,
University of Ottawa, Ottawa, Canada. 6Centre for Global Health, Institute of Population Health, University of Ottawa, Ottawa,
Canada. 7Epidemiology and Community Medicine, Ottawa Health Research Institute, Ottawa, Canada. 8Centre for Global Health,
Institute of Population Health, Department of Medicine, Ottawa Hospital, Ottawa, Canada
Contact address: George A Wells, Cardiovascular Research Reference Centre, University of Ottawa Heart Institute, Room H1-1, 40
Ruskin Street, Ottawa, Ontario, K1Y 4W7, Canada. [email protected].
Editorial group: Cochrane Musculoskeletal Group.
Publication status and date: Edited (no change to conclusions), published in Issue 7, 2010.
Review content assessed as up-to-date: 13 November 2007.
Citation: Wells GA, Cranney A, Peterson J, Boucher M, Shea B, Welch V, Coyle D, Tugwell P. Risedronate for the primary and
secondary prevention of osteoporotic fractures in postmenopausal women. Cochrane Database of Systematic Reviews 2008, Issue 1. Art.
No.: CD004523. DOI: 10.1002/14651858.CD004523.pub3.
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
A B S T R A C T
Background
Osteoporosis is an abnormal reduction in bone mass and bone deterioration leading to increased fracture risk. Risedronate belongs to
the bisphosphonate class of drugs which act to inhibit bone resorption by interfering with the activity of osteoclasts.
Objectives
To assess the efficacy of residronate in the primary and secondary prevention of osteoporotic fractures in postmenopausal women.
Search strategy
We searched CENTRAL, MEDLINE and EMBASE. Relevant randomized controlled trials published between 1966 to 2007 were
identified.
Selection criteria
Women receiving at least one year of risedronate for postmenopausal osteoporosis were compared to those receiving placebo or
concurrent calcium/vitamin D or both. The outcome was fracture incidence.
Data collection and analysis
We carried out study selection and data abstraction in duplicate. Study quality was assessed through the reporting of allocation
concealment, blinding and withdrawals. Meta-analysis was preformed using relative risks and a >15% relative change was considered
clinically important.
1Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
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Main results
Seven trials were included in the review representing 14,049 women.
Relative (RRR) and absolute (ARR) risk reductions for the 5 mg dose were as follows. Risk estimates for primary prevention were
available only for vertebral and non vertebral fractures and showed no statistically significant effect of risedronate on fractures. For
secondary prevention, a significant 39% RRR in vertebral fractures (RR 0.61, 95% CI 0.50 to 0.76) with 5% ARR was found. For non-
vertebral fractures, a significant 20% RRR (RR 0.80, 95% CI 0.72 to 0.90) with 2% ARR and for hip fractures there was a significant
26% RRR (RR: 0.74, 95% CI 0.59 to 0.94) with a 1% ARR. When primary and secondary prevention studies were combined, the
reduction in fractures remained statistically significant for both vertebral (RR 0.63, 0.51 to 0.77) and non vertebral fractures (RR 0.80,
0.72 to 0.90)
For adverse events, no statistically significant differences were found in any of the included studies. However, observational data has
led to concerns regarding the potential risk for upper gastrointestinal injury and, less commonly, osteonecrosis of the jaw.
Authors’ conclusions
At 5 mg/day a statistically significant and clinically important benefit in the secondary prevention of vertebral, non-vertebral and hip
fractures was observed, but not for wrist. The level of evidence for secondary prevention is Gold (www.cochranemsk.org) for vertebral
and non-vertebral and Silver for hip and wrist. There were no statistically significant reductions in the primary prevention of vertebral
and non-vertebral fractures. The level of evidence is Silver.
P L A I N L A N G U A G E S U M M A R Y
Risedronate for preventing fractures caused by osteoporosis in postmenopausal women
This summary of a Cochrane review, presents what we know from research about the effect of Risedronate for preventing fractures
(broken bones) caused by osteoporosis.
In women who have already been diagnosed with low bone density putting them at risk for fracture or have already had a
fracture in the bones of their spine, risedronate:
- probably prevents fractures in the bones of the spine and in bones other than in the spine;
- may prevent hip fractures;
- may not lead to any difference in wrist fractures.
In women whose bone density is closer to normal or who may not yet have had a fracture in the bones of their spine, risedronate:
may not lead to any difference in fractures in the bones of the spine, hip fractures or wrist fractures;
there is not enough information to tell if Risedronate prevents fractures in bones other than in the spine.
We do not have precise information about side effects and complications. This is particularly true for rare but serious side effects.
Possible side effects may include digestive problems such as damage to the throat, esophagus and stomach and, less commonly, reduced
blood supply to the jaw bone, which causes the bone tissue to breakdown .
What is osteoporosis and what is risedronate?
Bone is a living, growing part of your body. Throughout your lifetime, new bone cells grow and old bone cells break down to make
room for the new, stronger bone. When you have osteoporosis, the old bone breaks down faster than the new bone can replace it. As
this happens, the bones lose minerals (such as calcium). This makes bones weaker and more likely to break even after a minor injury,
like a little bump or fall. Women who have gone through menopause are more likely to get osteoporosis than other people.
2Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
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Risedronate belongs to the class of drugs called bisphosphonates. It is a type of medication that slows down the cells that break down
the old bone.
Best estimate of what happens to women that have already been diagnosed with low bone density putting them at risk for
fracture or have already had a fracture in the bones of their spine, who take Risedronate:
Fracture of the spine
- 14 out of 100 women had a fracture when taking a placebo
- 9 out of 100 women had a fracture when taking Risedronate
Fracture in the hip
- 3 out of 100 women had a fracture when taking a placebo
- 2 out of 100 women had a fracture when taking Risedronate
Fracture in the wrist
- 4 out of 100 women had a fracture when taking a placebo
- 3 out of 100 women had a fracture when taking Risedronate.
Fractures in bones other than the spine
- 10 out of 100 women had a fracture when taking a placebo
- 8 out of 100 women had a fracture when taking Risedronate
Best estimate of what happens to women whose bone density is closer to normal or who may not yet have had a fracture in the
bones of their spine who take risedronate:
- there is no difference in the number of women out of 100 who will have a spine fracture. This may be the result of chance.
- for hip and wrist fractures, it is not possible to calculate the effect because no one had fractures of the hip or wrist in the
studies.
- there is not enough information to tell if Risedronate prevents fractures in bones other than in the spine.
B A C K G R O U N D
Osteoporosis is in part a natural consequence of aging in post-
menopausal women (Hodsman 2002). It is a skeletal disorder char-
acterized by decreased bone mass and deterioration of microar-
chitecture of bone resulting in an increased risk of fracture (NIH
Consensus 2001).
The most common consequences of osteoporosis are fractures of
3Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
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the hip, wrist and vertebrae (Hodsman 2002). “Bone strength re-
flects the integration of two main features: bone density and bone
quality” (Brown 2002b). The clinical indicator of bone quality is a
patient’s history of a fragility fracture. A fragility fracture is a frac-
ture caused by an injury that would be insufficient to fracture nor-
mal bone (for example, a fall from a standing height or less)(Brown
2002b). The preferred method of evaluating bone density is the
measurement of bone mineral density (BMD) of the lumbar spine
and hip by Dual Energy X-ray Absorptiometry (DXA), which can
be used to assess response to therapy (Hanley 2003).
The interpretation of BMD results is based on comparison of a
patient’s BMD with the mean value for a young adult population.
The “T-score” is the number of standard deviations (SDs) above
or below the mean BMD for normal young adults (Brown 2002b).
The World Health Organization (WHO) Study Group on Os-
teoporosis defined osteoporosis as “a hip BMD level of more than
2.5 SDs below the mean BMD for young, white, adult women”
(WHO 1994). Using the WHO definition, approximately 30%
of postmenopausal women have osteoporosis (Kanis 1994; WHO
1994). It should be noted that there are limitations associated with
the WHO definition. The predictive value of BMD measurement
for fracture varies depending on the site selected, database used
for comparison and the technology used. Furthermore, T-scores
do not provide a good basis to establish comparable diagnostic
thresholds between different regions of interest and different bone
mass measurement techniques (Black 2001). As a result, between-
site and technique variability introduces potential for misclassifi-
cation and inappropriate treatment of some individuals.
Osteoporosis can be detected by BMD measurement or diagnosed
by presence of osteoporosis-related fractures. The presence of pre-
existing osteoporotic fractures is an important risk factor for future
fractures (Hodsman 2002). It is reported that 25% of women
aged 80 have had at least one vertebral fracture (Melton 1989)
and Cauley et al., (Cauley 2000) demonstrated excess mortality
in women who have experienced a clinical vertebral fracture. The
cumulative lifetime fracture risk for a 50-year-old woman with
osteoporosis is stated to be as high as 60% (Cummings 1989). As
a result, effective fracture prevention would have a major impact
on morbidity and a smaller but important impact on mortality in
these women.
Osteoporosis-related morbidity is associated with significant med-
ical and social consequences (Brown 2002b). The major source
of morbidity and mortality from osteoporosis is attributed to hip
fractures. Hip fractures are not only associated with an increase
mortality risk but also influence long-term function and indepen-
dence. Fifty per cent of women who sustain a hip fracture do not
return to their previous functional state and become dependent
on others for their daily activities (Brown 2002b). The mortality
associated with hip fractures in older women may be as high as
20% in the first year (Cauley 2000). This excess mortality may
not be directly attributable to the hip fracture, but to comorbid
conditions (Browner 1996; Cooper 1993).
Prevention and treatment of osteoporosis can be complex, due to
the multifactorial etiology of the disorder. New anabolic therapies
directed at increasing bone formation, such as teriparatide (recom-
binant human parathyroid hormone (1-34)), (Shukla 2003) are
available, however most currently available osteoporosis drugs are
anti-resorptive agents that act to decrease bone turnover. One class
of anti resorptive drugs includes the bisphosphonates: etidronate,
alendronate and risedronate. They are recommended as first-line
preventive agents in postmenopausal women with low BMD and
as first-line agents for the treatment of postmenopausal women
with osteoporosis (Brown 2002b).
Bisphosphonates are stable analogues of naturally occurring py-
rophosphates. The mechanism of action of these drugs is to in-
hibit bone resorption through their effects on osteoclasts (Brown
2002b). Bisphosphonates are poorly absorbed and avidly taken
up by bone on active sites of resorption. Risedronate is a nitro-
gen containing pyridinyl third generation bisphosphonate which
is administered daily or once weekly (depending on formulation).
The recommended dose for the prevention and treatment of os-
teoporosis in postmenopausal women is 5 mg/day (35 mg / week)
. Risedronate at 5 mg, relative to control, has been shown to in-
crease bone mineral density after 1.5 to three years of treatment
by 4.54% (95% CI 4.12 to 4.97) in the lumbar spine, and 2.75%
(95% CI 2.32 to 3.17) in the femoral neck (Cranney 2002). At
a dose of 2.5 mg increases at the lumbar spine and femoral neck
were 2.94% (95% CI 1.55 to 4.34) and 1.71%, (95% CI 1.17 to
2.25) (Cranney 2002).
O B J E C T I V E S
The aim of this systematic review was to assess the clinical effi-
cacy of risedronate in the primary and secondary prevention of
osteoporotic fractures in postmenopausal women receiving these
agents compared with untreated women over a follow-up period
of at least one year.
M E T H O D S
Criteria for considering studies for this review
Types of studies
Randomized controlled trials (RCTs) with a duration of at least
one year were included in this review.
4Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
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Types of participants
The population group of interest was post menopausal women.
Both primary and secondary prevention trials were accepted. A
hierarchy was used to define primary versus secondary prevention
according to the information available. We selected a definition of
primary and secondary prevention that gave more weight to study
inclusion criteria than baseline statistics. That is, if the inclusion
criteria restricted the population to women whose bone density
was at least 2 SD values below the peak bone mass or the inclu-
sion criteria restricted the population to women that had experi-
enced previous vertebral compression fractures, then the trial was
considered a secondary prevention study. If such inclusion criteria
were not provided then the baseline statistics were considered as
follows: (a) we considered the trial as primary prevention if the
average T-score (and SD) was such that it included women whose
bone density was within 2 SD of the mean or if the prevalence
of vertebral fracture at baseline was less than 20%; and (b) when
these data were not available, we considered a trial as secondary
prevention if the average age was above 62 years.
Types of interventions
Treatment: Risedronate at any dose.
Comparators: No treatment (including placebo or calcium or vita-
min D or both). If the study used calcium or vitamin D controls or
both, these same treatments would have to be given concurrently
in the risedronate treatment group.
Types of outcome measures
Incidence of fractures, including vertebral, non-vertebral, hip and
wrist fractures.
Search methods for identification of studies
The Cochrane Collaborative approach for identifying randomized
controlled trials (RCTs) as described by Dickersin et al., (Dickersin
1994) and modified for the Cochrane Musculoskeletal Group,
guided our literature search. We searched the Cochrane Cen-
tral Register of Controlled Trials (CENTRAL), MEDLINE from
1966 to November 2004, Current Contents, and citations of rel-
evant articles. No language restrictions were applied to the search
strategy. The actual literature search was conducted in three stages.
The first stage was the basis for our systematic review published
in 2002 (Cranney 2002) and the second and third stages involved
updating the search. The first search, for the time period 1966
to December 2000, included Cochrane Controlled Trials Regis-
ter, MEDLINE, EMBASE, Current Contents, and handsearching
of conference abstracts and FDA proceedings. This was followed
by a MEDLINE search for the time period 2000 to November
2004. This MEDLINE search was confirmed by a parallel litera-
ture search that was conducted for a companion bisphosphonate
economic report CADTH 2006. For the final update (2004 to
February 2007), we searched the Cochrane Central Register of
Controlled Trials (CENTRAL), MEDLINE and EMBASE.
Search Strategy MEDLINE Using OVID Interface
1. osteoporosis, postmenopausal/
2. osteoporosis/
3. osteoporosis.tw.
4. exp bone density/
5. bone loss$.tw.
6. (bone adj2 densit$).tw.
7. or/2-6
8. menopause/
9. post-menopaus$.tw.
10. postmenopaus$.tw.
11. or/8-10
12. 7 and 11
13. 1 or 12
14. risedronate.tw.
15. 13 and 14
16. meta-analysis.pt,sh.
17. (meta-anal: or metaanal:).tw.
18. (quantitativ: review: or quantitativ: overview:).tw.
19. (methodologic: review: or methodologic: overview:).tw.
20. (systematic: review: or systematic: overview).tw.
21. review.pt. and medline.tw.
22. or/16-21
23. 15 and 22
24. clinical trial.pt.
25. randomized controlled trial.pt.
26. tu.fs.
27. dt.fs.
28. random$.tw.
29. (double adj blind$).tw.
30. placebo$.tw.
31. or/24-30
32. 15 and 31
Data collection and analysis
Selection of studies
Two review authors examined each title generated from the search
and identified potentially eligible articles, for which we obtained
the abstracts. We obtained the full article text for abstracts consis-
tent with study eligibility. Overall, we only considered published
studies for inclusion, either as the full article or abstract.
Data abstraction strategy
Two independent review authors abstracted all information and
data using standardized data abstraction forms with a third review
author verifying the data. Abstraction included information on
pertinent methodological aspects of the study design, character-
istics of the participants, the specific dose of the study drug used
and the outcomes assessed (e.g. number of vertebral, non-verte-
5Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
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bral, hip and wrist fractures). For fracture data, we considered all
reported fractures (whether clinical or radiographic).
For the yearly data, our unit of analysis was number of patients
sustaining a fracture. If an article reported yearly data, we used
the time points available. For baseline denominators we used the
same baseline denominator for each time point. For follow-up
denominators we used any yearly follow-up number of patients
reported in the article, if available. If these were not available, we
assumed a uniform drop-out rate for each year and calculated the
denominators by determining the proportion of participants that
would have remained at the end of the year in question based
on the number of withdrawals over the course of the study. If
an article reported only end of study outcomes, these were used
for our analysis with the exception of outcomes for which the
numerator was zero for both treatment groups. In these instances,
we included the outcome (with any necessary adjustments for
follow-up denominators) for the earlier years in the duration of the
study. For example, if a trial reported zero hip fractures for both
treatment arms at the end of year three, we would also include in
our analysis zero hip fractures for that trial at years one and two.
For person year data, the unit of analysis, if available, was number
of fractures. When these data were not available (that is, in the
majority of cases), we used the number of women sustaining a
fracture. For denominators, we multiplied the number of women
followed by the length of the study. For radiographic vertebral frac-
tures we used the number of women with available radiographs,
if the number was reported in the article. For clinical fractures,
we estimated the number of women followed over the duration
of the study by taking the mean of the baseline and follow-up
denominators.
Strategy for quality assessment
Two review authors assessed each eligible RCT for quality based on
allocation concealment. Research has shown that lack of adequate
allocation concealment is associated with bias, (Higgins 2005) and
studies can be judged on the method of allocation concealment.
The method for assigning participants to interventions should be
robust against patient and clinician bias and its description should
be clear. The review authors were required to indicate whether
allocation concealment was adequate (A), unclear (B), or inade-
quate (C) as per the Cochrane Collaboration criteria as follows:
Adequate: The following are some approaches that can be used to
ensure adequate concealment schemes: centralized or pharmacy-
controlled randomization, pre-numbered or coded identical con-
tainers which are administered serially to participants, on-site com-
puter system combined with allocations kept in a locked unread-
able computer file that can be accessed only after the characteristics
of an enrolled participant have been entered or sequentially num-
bered or sealed, opaque envelopes. Other approaches may include
those similar to ones listed previously, along with reassurance that
the person who generated the allocation scheme did not adminis-
ter it.
Inadequate: Approaches to allocation concealment that are con-
sidered inadequate include: alternation, use of case record num-
bers, dates of birth or day of the week and any procedure that is
entirely transparent before allocation, such as an open list of ran-
dom numbers.
Unclear: When studies do not report any concealment approach,
adequacy should be considered unclear. Examples include merely
stating that a list or table were used, only specifying that sealed en-
velopes were used and reporting an apparently adequate conceal-
ment scheme in combination with other information that leads
the review author to be suspicious.
In addition, blinding and loss to follow up were assessed.
Data analysis
For the analysis of fractures (i.e. vertebral, non-vertebral, hip and
wrist), we calculated the relative risk (RR) of fracture using a fixed-
effect model. The methods we used for pooling the results are de-
scribed elsewhere by Fleiss, (Fleiss 1993). We calculated the pooled
or weighted RRs using the general inverse variance method for
the weights. For the pooled results, we calculated site-specific 95%
confidence intervals (CIs) for vertebral, non-vertebral, hip and
wrist fractures and we tested for association using a chi-squared
test procedure taking P value < 0.05 for presence of statistical as-
sociation. Statistically significant risk reductions were considered
to be clinically important if a 15% or greater relative benefit was
shown. We also tested for homogeneity using a chi-squared test
procedure taking the specific cut-off for presence of statistical het-
erogeneity as P = 0.10 ( Fleiss 1993). In the event of significant
heterogeneity, a random-effects model was used.
If the relative risk reduction (RRR) was significant (P < 0.05),
then the absolute risk reduction (ARR) and number needed to
treat to benefit (NNTB) were calculated. For these calculations,
the five year risk of fracture in the untreated population was based
on the FRACTURE Index (FI) of Black et al., (Black 2001) and
the lifetime and five year age-specific risks in the untreated popu-
lation were based on the model by Doherty et al., (Doherty 2001)
for predicting osteoporotic fractures in postmenopausal women
(Figure 1; Figure 2; Figure 3; Figure 4.)
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Figure 1. Models for fracture risk in postmenopausal women: FRACTURE Index
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Figure 2. Five year risk of fracture by Quintiles of the FRACTURE Index: Assessment with bone mineral
density
Figure 3. Five year risk of fracture by Quintiles of the FRACTURE Index: Assessment without bone mineral
density
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Figure 4. Estimated five year age-specific risks of first and subsequent osteoporotic fractures (from Doherty
et al 2001)
Trials varied as to the length of treatment (for example, one to four
years) and the number of patients available for study at the start
of treatment (that is, baseline denominator) compared to those
available at different time points during the trial (that is, follow-
up denominators). The base case taken for the review of fractures
considered the data available for the longest period of time for the
treatment in the trial (that is, “all years”) and used the baseline
denominators for the number of patients in the trial.
Data was initially pooled broadly across primary and secondary
trials. The overall analysis was also considered using person years of
observation. In addition, we conducted subgroup analysis for: 1)
primary versus secondary, 2) treatment duration and 3) treatment
dose. Furthermore, we conducted sensitivity analysis for: 1) base-
line denominators versus follow-up denominators, 2) fixed versus
random-effects model, and 3) baseline vertebral fracture rate. For
the last sensitivity analysis, recall that the vertebral fracture criteria
for a trial to be considered secondary was a prevalence of vertebral
fracture at baseline of greater than 20%. A sensitivity analysis us-
ing different vertebral fracture rates (i.e. 100%, > 80%, > 60%, >
40%, > 20%) without the BMD and age criteria was conducted.
Such sensitivity analysis allowed evaluating whether the effect of
bisphosphonates on the secondary prevention of osteoporotic frac-
tures varied, depending on how strictly secondary prevention was
defined.
Grading of evidence
Results from the primary analyses were graded according to the
system described in the 2004 book Evidence-based Rheumatol-
ogy (Tugwell 2004) and recommended by the Cochrane Muscu-
loskeletal Group:
Platinum
To achieve the platinum level of evidence, a published systematic
review that has at least two randomized controlled trials each sat-
isfying the following is required.
• Sample sizes of at least 50 per group - if these do not find a
statistically significant difference, they are adequately powered
for a 20% relative difference in the relevant outcome.
• Blinding of patients and assessors for outcomes.
• Handling of withdrawals > 80% follow up (imputations
based on methods such as Last Observation Carried Forward
(LOCF) are acceptable).
• Concealment of treatment allocation.
Gold
The gold level of evidence requires at least one randomized clinical
trial meeting all of the following criteria for the major outcome(s)
as reported:
• Sample sizes of at least 50 per group - if these do not find a
statistically significant difference, they are adequately powered
for a 20% relative difference in the relevant outcome.
• Blinding of patients and assessors for outcomes.
• Handling of withdrawals > 80% follow up (imputations
based on methods such as LOCF are acceptable).
• Concealment of treatment allocation.
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Silver
The silver level of evidence requires a randomized trial that does
not meet the above criteria for gold or platinum ranking or ev-
idence from at least one study of non-randomized cohorts that
did and did not receive the therapy, or evidence from at least one
high quality case-control study. A randomized trial with a ’head-
to-head’ comparison of agents would be considered silver level
ranking unless a reference were provided to a comparison of one
of the agents to placebo showing at least a 20% relative difference.
Bronze
The bronze level of evidence requires at least one high quality case
series without controls (including simple before/after studies in
which patients act as their own control) or a conclusion derived
from expert opinion based on clinical experience without reference
Clinical relevance tables
Clinical relevance tables were compiled under “Additional tables”
to improve the readability of the review. Results were presented
within the context of both the study population and moderate/
high risk women from the population at large. The number needed
to treat to benefit (NNTB) was calculated using the relative risk
(RR) in combination with either the risk of fracture in the control
group, or the five year FRACTURE Index (Black 2001). To do
this, the Visual Rx NNT calculator (Cates 2004) was used. The
weighted absolute risk difference was calculated using the risk
difference (RD) statistic in RevMan and RR-1 was used to calculate
the relative per cent change (Table 1; Table 2).
In addition, for the outcomes of vertebral and hip fractures we
prepared ’Summary of Findings tables using the GRADE criteria
from the GRADE working group (GRADE 2004), (Figure 5;
Figure 6).
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Figure 5. Summary of Findings for Primary Prevention
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Figure 6. Summary of Findings for Secondary Prevention
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R E S U L T S
Description of studies
See: Characteristics of included studies; Characteristics of excluded
studies.
Quantity of research available
The literature search revealed 419 citations as depicted in Figure 7.
Of these, 36 articles were retrieved for further scrutiny. A total of
29 articles were excluded for various reasons including lack of ap-
propriate control group (4), (Brown 2002b; Harris 2001b; Harris
1999b; Kushida 2004) lack of fracture outcome (8), (Delmas
1997; Dobnig 2006; Eriksen 2002; Hooper 1999; Hu 2005;
Leung 2005; Li 2005; Yildirim 2005) lack of appropriate frac-
ture data (that is, reported as adverse events and unspecified) (1),
(Hosking 2003) lack of randomization (5), (Goa 1998; Licata
1997; Reszka 1999; Singer 1995; Watts 1998) extension/discon-
tinuation study (2), (Sorensen 2003; Ste-Marie 2004) duplicate
report or earlier report of another study (7), (Eastell 2003; Miller
1999; Reginster 2001; Ribot 1999; Roux 2004; Watts 1999; Watts
2003) duration of therapy less than one year (1) (Zegels 2001) and
no extractable data (1). (McClung 1998 1) If duplicate reports of
the same study were found in preliminary abstracts and articles,
the data from the most complete data set was analyzed. In the end,
seven trials met the selection criteria (Clemmesen 1997; Fogelman
2000; Harris 1999; Hooper 2005; McClung 2001; Mortensen
1998; Reginster 2000). (See Figure 7.)
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Figure 7. Summary of literature search for risedronate
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Trial characteristics
The characteristics of the seven selected trials are provided in
the ’Characteristics of included studies’ table. In total, there were
14,049 women enrolled in these trials, and of these, 4746 re-
ceived placebo. Two trials were primary prevention (Hooper 2005;
Mortensen 1998) and the other five studied women with low
BMD on densitometry or who had experienced previous frac-
tures or both. (Clemmesen 1997; Fogelman 2000; Harris 1999;
McClung 2001; Reginster 2000) All trials had three treatment
arms that included two arms involving risedronate at different
doses (i.e. 2.5 mg or 5 mg) or different schedules or both and a
placebo arm. In our analysis, we did not include data from the
two risedronate arms in any single meta-analysis in order to avoid
duplication of data in the pooled estimates. In the case of the Mc-
Clung study, results were not reported separately in the form of
raw data for the 2.5 mg and 5 mg doses. We therefore used the
combined dose data in our primary 5 mg analysis. Length of fol-
low up ranged from two to three years and mean age was 51 to 78.
No trial excluded women with a history of gastrointestinal disease
and in three trials fractures were evaluated as the stated primary
outcome (Harris 1999; McClung 2001; Reginster 2000). All trials
with the exception of one (Mortensen 1998) administered 1000
mg of calcium to all patients. Three trials administered up to 500
IU of vitamin D (Harris 1999; McClung 2001; Reginster 2000).
Risk of bias in included studies
Treatment allocation was concealed in two trials (Harris 1999;
Hooper 2005) and was unclear for the other five . All seven trials
had losses to follow up that exceeded 20%. Two trials (Clemmesen
1997; Hooper 2005) had losses to follow up between 20 and 30%,
three trials between 30 and 40% (Fogelman 2000; Harris 1999;
McClung 2001) and two trials exceeded 40% (Mortensen 1998;
Reginster 2000). All trials were double blind.
Effects of interventions
Effect on fractures
A summary of the overall review of fractures with the standard dose
of risedronate (5 mg) for the base case (i.e. the longest treatment
duration in the trial and using the baseline denominators for the
number of patients) is provided in (Figure 8). Primary prevention
estimates were available only for vertebral and non- vertebral frac-
tures, neither of which were statistically significant. For each of
vertebral, non-vertebral, and hip fracture, the pooled estimate of
the RR of fracture was significant for secondary prevention. The
exception was wrist fracture, which was not significant.
Figure 8. Weighted relative risk of fracture after risedronate (5mg)
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Vertebral fractures
For primary prevention, Mortensen (Mortensen 1998) reported
no fractures leaving Hooper (Hooper 2005) as the only primary
prevention study reporting vertebral fractures. The estimate of the
RR was not statistically significant (RR 0.97, 95% CI 0.42 to
2.25).
Vertebral fractures were reported in four secondary prevention
trials (Clemmesen 1997; Fogelman 2000; Harris 1999; Reginster
2000). One study was not included in analysis due to the apparent
inclusion of an off-drug treatment period in the data (Clemmesen
1997). The pooled estimate of the RR of vertebral fractures from
the three trials (Fogelman 2000; Harris 1999; Reginster 2000) that
could be analyzed demonstrated a significant reduction (39%) in
vertebral fractures (RR 0.61, 95% CI 0.50 to 0.76) as detailed in
’Comparison 01, 01’. This demonstrates a fracture risk reduction
with risedronate 5 mg daily and results are consistent across studies
(P = 0.75).
For both primary and secondary prevention trials combined the
pooled estimate (RR 0.63, 95% CI 0.51 to 0.77) was similar to
that for that for secondary prevention alone
Corresponding to the significant RRR of 39% for the secondary
prevention of vertebral fractures, the absolute measures ARR and
NNT of the five year risk of vertebral fracture after treatment with
risedronate were calculated for different levels of increasing risk
as given by the FI. Results are provided in (Figure 9) as well as
for increasing age in (Figure 10). For the illustrative case of the
patient with a FI of 6 to 7, the ARR in vertebral fracture was
2.8% (that is, a reduction in risk from 7.1% to 4.3%) and the
NNTB was 36 (that is, 36 patients need to be treated to avoid one
vertebral fracture). Across the range of increasing FI risk, the ARR
for vertebral fracture ranged from 0.5% to 4.4% and the NNT
to avoid one vertebral fracture ranged from 214 to 23. For the
illustrative patient in the age group 60 to 64 years, the ARR for the
first vertebral fracture was 0.4% (that is, a reduction in risk from
1.0% to 0.6%) and the NNT was 256 patients treated to avoid the
first fracture. The ARR for a subsequent fracture was 3.8% (that
is, a reduction in risk from 9.7% to 5.9%) and the NNT was 26
patients treated to avoid one subsequent fracture. For increasing
age, the five-year age-specific ARR for the first vertebral fracture
increased from 0.1% for the youngest age group (50 to 54 years) to
1.8% in the highest age group (90+ years) and the NNT decreased
from 1282 to 55. For the subsequent fracture, ARR increased from
0.2% to 10.9% and the NNT decreased from 513 to 9.
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Figure 9. Five year FRACTURE Index specific risk of fracture after risedronate (5mg)
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Figure 10. Five year age-specific risk of first and subsequent fracture after risedronate (5 mg)
Non-vertebral fractures
One primary prevention trial (Hooper 2005) reported non-verte-
bral fractures. The risk estimate (RR 0.81, 95% CI 0.25 to 2.58)
was not statistically significant.
Non-vertebral fractures were reported in five secondary prevention
trials (Clemmesen 1997; Fogelman 2000; Harris 1999; McClung
2001; Reginster 2000). After excluding the study with a possible
off drug treatment period, the pooled estimate of the RR of non-
vertebral fractures from four trials (Fogelman 2000; Harris 1999;
McClung 2001; Reginster 2000) that could be analyzed demon-
strated a significant 20% reduction in non-vertebral fractures (RR
0.80, 95% CI 0.72 to 0.90). Results are provided in Comparison
02, 01 and they were consistent across studies (P = 0.43).
For both primary and secondary prevention trials combined the
pooled estimate (RR 0.80, 95% CI 0.72 to 0.90) was the same
that for that for secondary prevention alone as the Hooper trial
comprised only 1.04% of the total weight.
Corresponding to the significant RRR of 20% for the secondary
prevention of non-vertebral fractures, the absolute measure: ARR
and NNT of the five year risk of non-vertebral fracture after treat-
ment with risedronate were calculated for different levels of in-
creasing risk as given by the FI (Figure 9) and for increasing age
(Figure 10). For the illustrative case of the patient with a FI of 6 to
7, the ARR in non-vertebral fracture was 4.0% (that is, a reduction
in risk from 19.8% to 15.8%) and the NNT was 25 (that is, 25
patients need to be treated to avoid one non-vertebral fracture).
Across the range of increasing FI risk, the ARR for non-vertebral
fracture ranged from 1.7% to 5.5% and the NNT to avoid one
non-vertebral fracture ranged from 58 to 18. For the illustrative
patient in the age group 60 to 64 years, the ARR for the first non-
vertebral fracture was 0.6% (i.e. a reduction in risk from 3.1% to
2.5%) and the NNT was 161 patients treated to avoid the first
fracture. The ARR for a subsequent fracture was 1.2% (that is,
a reduction in risk from 6.2% to 5.0%) and the NNT was 81
patients treated to avoid one subsequent fracture. For increasing
age, the five year age-specific ARR for the first non-vertebral frac-
ture increased from 0.3% for the youngest age group (50 to 54
years) to 7.0% in the highest age group (90+ years). Accordingly,
the NNT decreased from 313 to 14. For the subsequent fracture,
ARR increased from 0.5% to 7.5% and NNT decreased from 192
to 13.
Hip fractures
Hip fractures were reported in three of the secondary prevention
trials (Harris 1999; McClung 2001; Reginster 2000). The pooled
estimate of the RR of hip fractures from the three trials showed
a significant 26% reduction in hip fractures (RR 0.74, 95% CI
0.59 to 0.94). Results are provided in Comparison 03, 01 and they
were consistent across trials (P = 0.95).
Corresponding to the significant RRR of 26% for the secondary
prevention of hip fractures, the absolute measures ARR and NNT
of the five year risk of hip fracture after treatment with risedronate
were calculated for different levels of increasing risk as given by the
FI (Figure 9) and for increasing age (Figure 10). For the illustrative
case of the patient with a FI of 6 to 7, the ARR for hip fracture
was 1.0% (that is, a reduction in risk from 3.9% to 2.9%) and the
18Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
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NNT was 99 (that is, 99 patients need to be treated to avoid one
hip fracture). Across the range of increasing FI risk, the ARR for
hip fracture ranged from 0.1% to 2.3% and the NNT to avoid one
hip fracture ranged from 962 to 44. For the illustrative patient in
the age group 60 to 64 years, the ARR for the first hip fracture was
0.05% (i.e. a reduction in risk from 0.2% to 0.15%) and the NNT
was 1923 patients treated to avoid the first fracture. The ARR and
NNT for a subsequent fracture were the same. For increasing age,
the five year age-specific ARR for the first hip fracture increased
from less than 0.05% for the youngest age group (50 to 54 years) to
5.4% in the highest age group (90+ years) and the NNT decreased
from more than 1923 to 18. For the subsequent fracture, ARR
increased from less than 0.05% to 5.9% and the NNT decreased
from more than 962 to 17.
Wrist fractures
Wrist fractures were reported in two of the secondary trials (Harris
1999; Reginster 2000). The pooled estimate of the RR of wrist
fractures from the two trials showed a 33% reduction which was
not significant (RR 0.67, 95% CI 0.42 to 1.07). Results are given
in Comparison 04, 01 and they were consistent across trials (P =
0.81).
Additional analysis
Person years
Results were similar for vertebral, non-vertebral, hip and wrist
fractures when using person years as depicted in (Figure 11). Of
note, the pooled estimates of the RR for the secondary prevention
trials all showed a significant risk reduction of fracture, with the
exception of wrist fractures.
Subgroup analysis
Treatment duration
No trends over years of treatments were found that deviated from
the overall RR estimates. For details, please refer to Figure 12 and
’Comparisons 05, 01; 06, 01; 07, 01; 08, 01; 09, 01; 10, 01; 11,
01’.
Figure 11. Weighted relative risk (RR) of fracture after risedronate (5 mg): Person years
19Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
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Figure 12. Weighted relative risk of fracture after risedronate (5 mg) by years of treatment
Treatment dose
For risedronate 2.5 mg, fracture data were only available for ver-
tebral and non-vertebral sites. There was no protective effect ob-
served for the primary prevention of vertebral fractures. For the
secondary prevention trials, the decrease in risk of vertebral frac-
ture was significant and there was a further, albeit slight, decrease
in risk with the 2.5 mg dose, compared with 5 mg (Figure 13;
Figure 14; Figure 15; Comparison 12, 01; Comparison 12, 02).
For non-vertebral fractures, the decrease in risk was not statisti-
cally significant for either primary or secondary prevention but
was more pronounced with the 2.5 mg dose compared with 5 mg.
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Figure 13. Weighted relative risk of fracture after risedronate by dose
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Figure 14. Weighted relative risk of fracture after risedronate by dose: Person years
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Figure 15. Weighted relative risk of fracture after risedronate by years of treatment and dose
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Sensitivity analysis
Baseline versus follow-up denominators
By using the data available for the longest treatment duration,
standard dose of risedronate (5 mg) and follow-up denominators
for the number of patients in the trials, a summary of the overall
review of fractures was prepared (Figure 16). These data are also
provided by years of treatment (Figure 17). The pooled estimates
of the RR of fracture after risedronate were essentially the same as
those obtained using the baseline denominators, with the excep-
tion that the pooled estimate of the RR of wrist fractures from two
secondary prevention trials (Harris 1999; Reginster 2000) demon-
strated a significant reduction (39%) in wrist fractures (RR 0.61,
95% CI 0.38 to 0.96) for risedronate 5 mg.
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Figure 16. Weighted relative risk of fracture after risedronate by dose: Follow-up denominators
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Figure 17. Weighted relative risk of fracture after risedronate by years of treatment and dose: Follow-up
denominators
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Random versus fixed-effect model
There were a few instances where heterogeneity of the trial results
was such that a random-effects model was needed (that is, only
involving the person years analysis). In general, results obtained
using the random and fixed-effect models were similar.
Baseline vertebral fracture rate
Using different baseline vertebral fracture rates (i.e. 100%, > 80%,
> 60%, > 40%, > 20%) for defining secondary trials, a summary
of the overall review of fractures was prepared (Figure 18). For
vertebral, non-vertebral and wrist fractures, the pooled estimates
of the RR of fracture after risedronate were essentially the same as
those obtained using the definition of secondary trials with the >
20% baseline fracture rate. Although the result for hip fractures
became non-significant when the criteria increased from > 40%
to > 60%, the relative risk of fracture was about the same (0.74
compared to 0.81) but the confidence interval was now wider since
the large 2001 trial by McClung et al (McClung 2001) with over
6000 participants was excluded from the analysis.
Figure 18. Weighted relative risk (RR) of fracture after risedronate (5 mg): sensitivity analysis by baseline
prevalent vertebral fracture rate
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Adverse events
A summary of the adverse drug reactions reported in the six ran-
domized placebo-controlled trials of risedronate is provided in
Figure 19; Figure 20; Figure 21 and Figure 22. In general, the
reported events were similar between risedronate and placebo. In
particular, there were five studies reporting ’any upper gastroin-
testinal events’ resulting in an overall RR 1.01 (95% CI 0.94 to
1.09) and four studies reporting ’esophageal ulcer’ resulting in an
overall RR 0.75 (95% CI 0.39 to 1.47).
Figure 19. Summary of adverse drug events reported in randomized placebo-controlled trials of
risedronate (part 1)
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Figure 20. Summary of adverse drug events reported in randomized placebo-controlled trials of
risedronate (part 2)
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Figure 21. Summary of adverse drug events reported in randomized placebo-controlled trials of
risedronate (part 3
Figure 22. Summary of adverse drug events reported in randomized placebo-controlled trials of
risedronate (part 4)
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Toxicity and withdrawals
Discontinuations due to adverse events or dropouts overall
were available and analyzed for five (Fogelman 2000; Harris
1999; Hooper 2005; McClung 2001; Reginster 2000) and six
(Clemmesen 1997; Fogelman 2000; Harris 1999; Hooper 2005;
McClung 2001; Reginster 2000) of the risedronate trials respec-
tively. The pooled estimate demonstrated no statistical difference
between risedronate and placebo for the risk of discontinuing med-
ication due to adverse events (RR 0.96, 95% CI 0.88 to 1.05) or
for dropouts overall (RR 0.96, 95% CI 0.91 to 1.00) (Comparison
13.01, 13.02). Results were consistent across the trials.
D I S C U S S I O N
Based on longest treatment duration and use of baseline denom-
inators for the number of patients in each of the included trials,
risedronate at 5 mg per day was associated with a statistically sig-
nificant and clinically important reduction in the secondary pre-
vention of vertebral, non-vertebral and hip fractures but not wrist.
The level of evidence was Gold for vertebral and non-vertebral
fractures and Silver for hip and wrist. For primary prevention, one
trial reported vertebral and non-vertebral fractures but no statisti-
cally significant reductions were found (Silver level evidence).
Secondary analyses showed that a dose of 2.5 mg, for secondary
prevention resulted in a statistically significant and clinically im-
portant reduction in vertebral fractures that is comparable to that
of the 5 mg dose (Gold level evidence). Only one primary pre-
vention trial reported vertebral fractures for the 2.5 mg dose and
no reduction was found (Silver level evidence). For non-vertebral
fractures, no statistically significant reductions were shown for ei-
ther primary or secondary prevention (Silver level evidence). In the
case of hip fractures, McClung et al (2001), randomized women
to receive placebo, 2.5 mg risedronate or 5.0 mg risedronate. This
was done separately for younger (70 to 79 years) and older (80 +
years) women. Although the results were not generally reported
separately by dose and age groups, the authors did note that the
effects of dose (2.5 mg versus 5.0 mg) for the younger age group
were similar (for 2.5 mg RR 0.5 (95% CI 0.3 to 0.9); for 5 mg RR
0.7 (95% CI 0.4 to 1.1). There were no trials available to assess
the efficacy of the 2.5 mg dose for wrist fractures.
There were no substantive differences in the results whether base-
line, end of study, or person year denominators were used. Sensi-
tivity analyses indicated that there were no major differences based
on the percentage of baseline vertebral fractures. Further, no trends
were found for years of treatment.
Adverse drug events observed with risedronate were similar to the
ones observed with placebo. The use of risedronate was not asso-
ciated with any statistically significant difference in withdrawals
due to adverse events (RR 0.96; 95% CI 0.88 to 1.05) or overall
withdrawals (RR 0.96; 95% CI 0.91 to 1.00), when compared to
placebo. In keeping with this, it was concluded that study partici-
pants tolerated their risedronate treatment. Although no increased
incidence of adverse effects were detected with risedronate, exter-
nal to the randomized controlled trials, concerns exist regarding
the potential risk of upper gastrointestinal events and osteonecro-
sis of the jaw.
Study limitations
The results of this systematic review are believed to be robust, as
we performed a comprehensive literature search, inclusion and ex-
clusion criteria were specified and we conducted a rigorous data
analysis. A potential limitation of our approach may be that the
update search (that is, 2000 to 2004) did not include non-MED-
LINE indexed journals. Recent empirical evidence indicates that
this approach may have introduced a slight risk of bias into our
meta-analysis. On average, such bias is estimated to result in a 6%
variation in the pooled results (Egger 2003; Sampson 2003). Ac-
cordingly, given that the initial literature search (that is, 1966 to
2000) was very extensive, the impact of only using MEDLINE for
the search update is expected to be minimal, if any. This was con-
firmed by a parallel literature search update (that is, 1999 to July
2004) that was conducted for an economic report for the Canadian
Agency for Drugs and Technologies in Health. The search update
included etidronate, alendronate and risedronate (daily dose reg-
imen only) in addition to teriparatide. We searched a number of
databases (i.e. The Cochrane Library, MEDLINE, EMBASE, BIO-
SIS Previews, Toxfile, PubMed) and no additional articles meeting
the inclusion criteria were identified (CADTH 2006).
While our methodology was robust, the results of our meta-analy-
sis, however, are only as strong as the primary studies included. In
keeping with this, the main limitations with regard to study qual-
ity were fracture assessment and classification, the lack of clarity of
the concealment of allocation and large numbers of withdrawals.
A potential source of heterogeneity is the lack of uniform defini-
tion of non-vertebral fracture. While some researchers may use a
rather liberal definition (any fracture other than vertebral fracture),
others may use a more conservative definition which includes only
fractures of the hip, clavicle, humerus, wrist, pelvis or leg (Mayo
Clin Proc 2005). Also, the statistical power to detect heterogeneity
was extremely limited for some tests due to the low number of
fractures in some categories. Another consideration is the fact that
fracture data was not the primary outcome for some of the trials. In
particular, four of the seven risedronate trials had fractures as the
primary outcome. There is another source of heterogeneity, and
possible bias, related to some of the secondary prevention stud-
ies. It concerns the inclusion of participants with a low BMD but
no proven fractures and the difficulty in discriminating between
fracture types (traumatic versus pathological). Also, at times, our
criteria for categorizing a study as a secondary prevention trial dif-
fered from those used by study investigators. An example is the
study by McClung et al (McClung 2001) which included two
31Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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age subgroups. In our review, we considered that both subgroups
evaluated the effect of risedronate in secondary prevention of os-
teoporotic fractures, although we acknowledge study investigators
may not have intended the same. However both subgroups sat-
isfied two of our secondary prevention criteria, that is, baseline
fracture rate and age. Indeed, both age subgroups had a baseline
fracture rate > 20% (primary prevention studies were required to
have a baseline fracture rate of < 20%). In addition, study partic-
ipants in both subgroups were over 62 years of age (we consid-
ered a trial as secondary prevention if the average age was above
62 years). Finally, the exploration of differences in effect between
primary and secondary prevention trials was a particular concern
in our review.
Another methodological limitation concerns the approach used
for concealment of treatment allocation which was not reported
for most trials (that is, classified as ’unclear’). Treatment allocation
was concealed in two trials (Harris 1999; Hooper 2005) and was
unclear for the other five trials.
The length of follow up in the studies (two to three years) is
an additional limitation. It is difficult to extrapolate beyond the
duration of the follow-up trials in the review with respect to the
long-term impact on fractures. Ultimately, data from longer-term
trials will help establish if the effect on fractures is maintained,
increased or diminished.
In regards to our own methodology, we acknowledge that the ap-
proach used to evaluate the effect of bisphosphonates over time
may result in some estimates that are not robust. In particular,
in order to determine the effect on the five year risk of fracture
we based our evaluation on the FRACTURE Index by Black et
al. (Black 2001) and for lifetime and five year age-specific risks
we used an existing model from Doherty et al. (Doherty 2001).
Although this latter approach allowed us to estimate the variation
in risks between younger and older postmenopausal women, these
estimates may be associated with a certain level of uncertainty.
Nonetheless, we believe such information may be useful to deci-
sion-makers.
Lastly, a limitation of evaluating data on adverse effects from sum-
mary meta-analyses is that participants in RCTs tend to be health-
ier with fewer co-morbid diseases and therefore the results may not
be generalizable to clinical practice. None of the six risedronate
trials, however, explicitly excluded patients with pre existing GI
disorders. Furthermore, RCTs are underpowered for rare effects
and meta-analyses of these trials generally cannot provide con-
clusive information pertaining to drug toxicity. In addition, the
heterogeneity of the adverse drug events (ADEs) reported in the
RCTs described in this review, including their nature, low occur-
rence, and way they were assessed by investigators, were obstacles
for meta-analysis. As well, the follow up for the included trials,
which ranged between one and three years, does not allow for the
assessment of long term toxicity associated with risedronate.
Recently, there have been concerns regarding the potential risk of
over suppressing bone turnover resulting in osteonecrosis of the
jaw (ONJ), (Khosla 2007; Woo 2006). Although the majority of
reported cases of ONJ have occurred in cancer patients receiv-
ing the intravenous bisphosphonates zolendrate or pamidronate
(at higher cumulative doses than used in the treatment of post-
menopausal osteoporosis), some osteoporosis patients receiving
oral alendronate or risedronate have developed the condition as
well. In a systematic review of cases reported in the medical litera-
ture, 13 of 368 bisphosphonate treated ONJ patients had received
alendronate and one risedronate (Woo 2006). Since that publica-
tion, a review conducted by the American Society for Bone and
Mineral Research (ASBMR) Task Force on Bisphosphonate-Asso-
ciated ONJ has identified studies reporting a total of 67 cases (64
alendronate, 2 risedronate and 1 etidronate) among osteoporosis
and Paget’s disease patients (Khosla 2007). Most notably, an Aus-
tralian study reported 30 of 114 ONJ cases related to alendronate
(22 of whom were under treatment for osteoporosis) and 2 related
to risedronate. The median time to onset, for alendronate, was 24
months. The most common triggering factor was dental extrac-
tion (Mavrokokki 2007). The ASBMR task force has pointed out
that the incidence of ONJ in the general population not exposed
to bisphosphonates is unknown, information on the incidence of
ONJ is rapidly evolving and that, often, the case ascertainment
has bee inadequate. They recommend that a hierarchy of evidence
quality, based on the completeness of information across seven
categories related to diagnosis and history, should be established
for all future studies reporting cases of ONJ (Khosla 2007). No
cases of ONJ were reported in any of the risedronate trials in our
review.
Finally, because RCTs are not designed to measure ADEs, partic-
ularly rare ones, it is common practice to include sources of infor-
mation other than RCTs. While some reviewers include ADEs re-
ported in observational studies, we elected to obtain information
from the Canadian Adverse Drug Reaction Monitoring Program
(CADRMP, see below) (Health Canada 2005).
Generalizability of findings
Generalizability of our findings is limited by the controlled de-
sign of the trials included in our review. Study participants were
carefully selected in these trials and so utilization of the drugs in
real life may vary substantially from study conditions. Further-
more, study participants were observed for periods of time varying
from one to three years. Consequently, while our results provide
support for efficacy (that is, can the intervention have an effect
on outcome?) they may possibly only provide partial information
on the long-term effectiveness (that is, does the intervention have
an effect on outcome?) of bisphosphonates in preventing osteo-
porotic fractures.
32Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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From a safety perspective, we could not find any statistically sig-
nificant difference in either the rates of adverse drug events or
withdrawal rates due to adverse drug events between patients re-
ceiving a bisphosphonate or patients receiving a placebo. How-
ever, outside controlled trials, concerns exist regarding the safe
use of these drugs, especially alendronate and, to a lesser extent,
risedronate, for which esophageal ulcers and gastritis have been
reported (Kherani 2002). While such adverse events have mainly
been identified through case reports and endoscopic studies, sim-
ilar concerns are also reflected in the proportions of gastrointesti-
nal adverse drug reactions associated with the use of risedronate
reported to the CADRMP (Health Canada 2005). Indeed, GI
adverse drug reactions represented 35% of reports for risedronate
(Figure 23). These proportions should however be interpreted with
caution as adverse drug reactions are reported to CADRMP on a
volunteer basis by health professionals, which means that several
reactions may be unreported. Indeed, it is estimated that less than
10% of adverse reactions are reported to Health Canada (Health
Canada 2005c). Also, a definite cause-effect relationship has not
been established for these adverse drug reactions.
33Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Figure 23. Adverse drug reactions reported to CADRMP for etidronate, alendronate and risedronate
A U T H O R S ’ C O N C L U S I O N SImplications for practice
Risedronate demonstrated a clinically important benefit in the sec-
ondary prevention of the majority of osteoporotic fractures. At a
dose of 5 mg per day, statistically significant reductions in verte-
bral, non-vertebral and hip fractures were observed (but not wrist).
No statistically significant reduction in the primary prevention of
vertebral and non-vertebral fractures and no evidence was available
for the primary prevention of hip or wrist fractures. No increased
incidence of adverse effects were detected with risedronate, but
34Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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clinicians should be aware that outside of randomized controlled
trials, concerns exist regarding the potential risk of upper gastroin-
testinal events and, less commonly, osteonecrosis of the jaw.
The prevention of osteoporotic fractures is an important public
health intervention. This is particularly true for hip and clinical
vertebral fractures (i.e. fractures of the spine that present for med-
ical attention). The RR of death following such fractures is six- to
nine-fold greater in postmenopausal women aged 55 to 81 years
with low BMD, which represents a typical postmenopausal pop-
ulation (Cauley 2000). In most cases, the mortality increase re-
flects poor underlying health status and comorbidity in addition
to the fracture itself (Cauley 2000). Osteoporotic fractures are also
associated with increase in morbidity, as it is reported that 50%
of women who sustain a hip fracture do not return to their usual
daily activities (Brown 2002b) while 33% will require long-term
care. Accordingly, reducing the incidence of such fractures can po-
tentially increase the quality of life of patients with osteoporosis.
Such interventions may also potentially decrease mortality.
Implications for research
It has been suggested from clinical trials with the bisphosphonates
(Black 2000; Harris 1999; McClung 2001) that their effect in
reducing non-vertebral fractures may be greater in patients with
lower BMD who initiate treatment. The existing data have not
fully resolved the question of whether important differences in
risk reduction across groups of patients with varying degrees of
osteoporosis exist. The impact of risedronate on the RR of non-
vertebral fractures in populations without osteoporosis also merits
further investigation. Additional research is also needed to clarify
the role of risedronate in the primary prevention of osteoporotic
fractures. There is also a need for additional post marketing sa-
fety data. Finally, research into combination therapy with higher
doses of vitamin D or anabolic agents would be merited as would
research concerning adherence to bisphosphonate therapy.
Given the morbidity consequences associated with osteoporotic
fractures, preventing their recurrence can potentially lessen the
need for community-based health services (for example, home
care). It may also reduce or delay the demand for long-term care
beds. However, very little comparative information is currently
available to support this (Hodsman 2002). There is also a lack of
studies which evaluated the effect of bisphosphonates on hospital
admissions (Hodsman 2002).
A C K N O W L E D G E M E N T S
Thank you to Lara Maxwell and Marie Andree Nowlan from the
Musculoskeletal Group for their editorial assistance and Tamara
Rader for her assistance with the Consumer Summaries.
R E F E R E N C E S
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C, Reginster JY. A 2-year phase II study with 1-year of
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35Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
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JD, Bolognese MA, et al.The efficacy and tolerability of
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36Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
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tolerated in postmenopausal women with low bone mineral
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Mavrokokki T, Cheng A, Stein B, Gross A. Nature and
Frequency of Bisphosphonate-Associated Osteonecrosis of
the Jaws in Australia. Journal of Oral Maxillofacial Surgery
2007;65:415–23.
Mayo Clin Proc 2005
Alendronate and vertebral fracture risk [multiple letters].
Mayo Clinic Proceedings 2005;80:1233–41.
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Melton LJ, III, Kan SH, Frye MA, Wahner HW, O’Fallon
WM, Riggs BL. Epidemiology of vertebral fractures in
women. American Journal of Epidemiology 1989;129(5):
1000–11.
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Prevention, Diagnosis, Therapy. Osteoporosis prevention,
diagnosis, and therapy. JAMA 2001;285(6):785–95.
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38Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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References to other published versions of this review
CADTH 2006b
Wells GA, Cranney A, Bouchere M, Peterson J, Shea
B, Robinson V, et al.Bisphosphonates for the primary
and secondary prevention of osteoporotic fractures in
postmenopausal women: a meta-analysis [Technology
report no 69]. Ottawa: Canadian Agency for Drugs and
Technologies in Health 2006.∗ Indicates the major publication for the study
39Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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C H A R A C T E R I S T I C S O F S T U D I E S
Characteristics of included studies [ordered by study ID]
Clemmesen 1997
Methods Randomized controlled trial
Secondary prevention
Blinding: double blind unspecified
Study length: 2 years
on drug plus 3rd
year drug free follow up
Withdrawals:
Continuous: 15/44 (34.1%)
Cyclic: 11/44 (25.0%)
Placebo: 13/44 (29.5%)
Total: 39/132 (29.5%)
Participants Source: Outpatients attending clinics which specialized in osteoporosis. Study was carried out in two
centres one in Denmark and one in Belgium
Inclusion Criteria: Healthy age 53-81, postmenopausal at least 1 year. Had at least one but no more than
4 vertebral fractures and at least 3 intact lumbar vertebrae
Exclusion Criteria: Estrogen or calcitonin within 12 mos, any bisphosphonate or fluoride, medications
affecting bone metabolism, secondary causes of osteoporosis.
Treatment N: 44, 44
Control N: 44
Age: 68.3 (5.7); YSM: 20.3 (7.3)
Calcium: not reported
BMD: 0.78 (0.14) g/cm2
T-score: -2.4
Fractures: 100%
Interventions Risedronate 2.5 mg/day or cyclical risedronate 2.5 mg/day for 2 wk followed by placebo for 10 wk vs.
placebo
(Calcium 1000 mg/day)
Outcomes This study was not included in the analysis as the assessment period for fractures appeared to include the
off drug treatment period
Vertebral Fractures: Lateral thoracic and lumbar radiographs performed under standardized conditions. At
the end of study radiographs were displayed simultaneously in chronological order for masked assessment
of vertebrae T4 to L5. Vertebral anterior and posterior heights were measured to the nearest millimetre
with a transparent ruler. Belgian site incident fractures were defined as = 15% height reduction in anterior
to posterior ratio or in the anterior or posterior wall as compared to adjacent vertebrae. For the Danish
site the reduction was 25%
Non-vertebral Fractures: Subjects reported all adverse events and were questioned about intercurrent
symptoms and illnesses at every visit
Notes
Risk of bias
40Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
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Clemmesen 1997 (Continued)
Item Authors’ judgement Description
Allocation concealment? Unclear B - Unclear
Fogelman 2000
Methods Randomized controlled trial
Secondary prevention
Blinding: double blind unspecified
Study length: 2
(2.5 mg patients from 9 of 13 centres (N = 76) discontinued prior to the end of the study due to protocol
amendment.)
Withdrawals:
2.5 mg: 111/184 (60.0%)
5.0 mg: 38/177 (21.5%)
Placebo: 37/180 (20.6%)
Total: 186/543 (34.3%)
[not including protocol amendment: 110/467 (23.6%)]
Participants Source: 13 centres in France, UK, the Netherlands, Belgium and Germany
Inclusion Criteria: Women up to 80 years who had been postmenopausal 1 year. Mean lumbar T-score
of -2 or less
Exclusion Criteria: Hyperthyroidism, hyperparathyroidism, or osteomalacia within 1 year, cancer, abnor-
malities affecting lumbar BMD measurement, drugs within 6 - 12 months affecting bone metabolism
including parenteral Vitamin D = 10,000 IU.
Note: patients with previous or ongoing upper GI disease were not excluded
Treatment N: 184, 177
Control N: 180
Age: 64.7 (7.2); YSM: 17.7 (9.4)
Calcium: not reported
BMD: 0.74 (0.08)
t-score: -2.9
Fractures: 30%
Interventions Risedronate 2.5 mg/day or risedronate 5 mg/day vs. placebo.
(Calcium 1000 mg/day)
Outcomes Vertebral Fractures: Lateral and anterior-posterior thoracic and lumbar (T4-L4) radiographs were taken
at baseline and lateral radiographs taken at end of study. Fractures were identified by quantitative mor-
phometry guidelines of US National Osteoporosis Foundation
Working Group on Vertebral Fractures and verified by a radiologist. A fracture was defined by any vertebral
height ratio falling 3 SD of the study population mean
Non-Vertebral: Adverse events (including vertebral and non-vertebral fractures) were assessed throughout
the study via spontaneous reports and direct questioning
Notes
Risk of bias
41Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
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Fogelman 2000 (Continued)
Item Authors’ judgement Description
Allocation concealment? Unclear B - Unclear
Harris 1999
Methods Randomized controlled trial
Secondary prevention
Blinding: double blind, identical placebo, investigators and other study personnel remained blinded
Study length: 3
(2.5 mg/day dose discontinued at 1 year due to protocol amendment.)
Withdrawals:2.5 mg: 238/817 (29.1%)
5.0 mg: 332/821 (40.4%)
Placebo: 370/820 (45.1%)
Total: 940/2458 (38.2%)
Participants Source: 110 centres in North America
Inclusion Criteria: Ambulatory women up to 85 years old who had been post menopausal at least 5 years.
Minimum two radiographically confirmed vertebral T4-L4 fractures (ratio of anterior or middle vertebral
height to the posterior height was = 0.8) or 1 vertebral fracture and lumbar BMD T-score = -2SD of
young adult (0.83g/cm² Hologic or 0.94g/cm² Lunar)
Exclusion Criteria: Conditions that could interfere with evaluation of spinal osteoporosis, calcitonin,
calcitriol or Vitamin D within one month, anabolic steroids, or HRT within 3 months, bisphosphonates,
fluoride within 6 months.
Note: Patients with previous or ongoing upper GI disease or use of medications associated with GI
intolerance (NSAIDS or asprin) were not excluded.
Treatment N: 817
Control N: 821, 820
Age: 69 (7.3); YSM: 24 (9.9)
Calcium: not reported
BMD: 0.83 g/cm2 (0.16)
t-score: -2.4
Fractures: 81%
Interventions Risedronate 2.5 mg/day or risedronate 5 mg/day vs. placebo.
(Calcium 1000 mg/day and if 25-hydroxyvitamin D level was < 40 nmol/L they received up to 500 IU/
day cholecalciferol
Outcomes Vertebral Fractures: Lateral thoracolumbar T4-L4 spine radiographs were obtained at baseline and annu-
ally. Prevalent and incident fractures were diagnosed quantitatively and semi-quantitatively. Quantitative
assessment defined an incident fracture as a 15% decrease of anterior, posterior or middle vertebral height
in a vertebra that was normal at baseline. In the semiquantitative assessment a new fracture was diagnosed
if the grade changed from 0 (normal) to 1(mild) 2 (moderate), or 3 (severe). An independent radiologist
adjudicated discrepancies between methods. Radiologists were blinded
Non-vertebral Fractures: Radiographically confirmed fractures of the clavicle, humerus, wrist, pelvis, hip
or leg, regardless of relationship to trauma
Notes
42Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
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Harris 1999 (Continued)
Risk of bias
Item Authors’ judgement Description
Allocation concealment? Yes A - Adequate
Hooper 2005
Methods Randomized controlled trial
Primary prevention
Blinding: double blind, matching placebo
Study length: 2 years
Withdrawals:
Risedronate 2.5 mg: 28/128 (21.9%)
Risedronate 5 mg: 26/129 (20.2%)
Placebo: 33/126 (26.2%)
Total: 87/383 (22.8%)
Participants Source: 11 centres in Australia.
Inclusion Criteria: Healthy women who were post menopausal 6- 36 months age with FSH > 50 MIU/
ml, and estradiol < 20 pg/ml. BMD T score > -2.5 (0.76g/cm2 Hologic or 0.8 g/cm2 Lunar). Exclusion
Criteria: Hyperparathyroidism, hyperthyroidism, osteomalacia or treatments affecting bone metabolism.
Patients not excluded due to GI disease or medications with potential to irritate GI tract
Treatment N: 2.5 mg 127, 5 mg 129
Control N: 125
Age: 52.6 (3.3); YSM 3.9 (5.6)
Calcium: not reported
BMD: 1.079 (12)
t-score: -0.410 (-0.1073)
Fractures: 18.3%
Interventions Risedronate 2.5 mg/day or 5.0 mg/day vs. placebo
(Calcium 1000 mg/day)
Outcomes Vertebral Fractures: Lumbar and thoracic lateral and anterior-posterior radiographs were taken at baseline
and 2 years. Deformity was confirmed by visual inspection and defined as vertebral height ratio below 3
SD of study population mean. Incident fracture was defined as a loss of 14% or more in anterior, posterior
or middle vertebral height in a vertebra that was normal at baseline
Non-vertebral Fractures: Were monitered as adverse events. At each visit patients were questioned regarding
medically related changes in well being with particular attention to fractures and GI events
Notes
Risk of bias
Item Authors’ judgement Description
43Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
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Hooper 2005 (Continued)
Allocation concealment? Yes A - Adequate
McClung 2001
Methods Randomized controlled trial
Secondary prevention
Blinding: double blind, identical placebo
Study length: 3 years
Withdrawals:2.5/ 5.0 mg combined: 2197/6197 (35.5%)
placebo: 1127/3134 (35.9%)
Total: 3324/9331 (35.6%)
Participants Source: 2 cohorts from 183 centres in North America, Europe, New Zealand and Australia
Inclusion Criteria: Group 1 - Women age 70-79 with osteoporosis defined as femoral neck BMD T-score
> 4 SD below peak bone mass (originally calculated according to densitometer reference data base and
later according to Third National Health and Nutrition Examination Survey) or > -3 SD and at least
one clinical risk factor i.e. difficulty standing from a sitting position, poor tandem gait, fall-related injury
in previous year, psychomotor score = 5 on Clifton Modified Gibson Spiral Maze test, smoking during
previous 5 years, maternal history of hip fracture, previous hip fracture, hip axis length = 11.1cm.
Group 2 - Women age 80 or older with at least one non-skeletal risk factor for hip fracture, a femoral-
neck t score < -4 or a femoral-neck t score < -3 plus a hip axis length = 11.1cm
Exclusion Criteria: Major medical illness, recent history of cancer, another metabolic bone disease within
1 year, important lab test abnormalities, recent drugs affecting bone, allergy to bisphosphonates, bilateral
hip fractures.
Note: Patients with previous or ongoing upper GI or use of medications associated with GI intolerance
(NSAIDS, asprin, proton pump inhibitors or antacids) were not excluded
Treatment N: 3093, 3104
Control N: 3134
Age: 78.0 (9.7); YSM: 31.8 (19.3)
Calcium: not reported
BMD: not reported
t-score (femoral): -3.7
Fractures: 42%
Interventions Risedronate 2.5 mg/day or risedronate 5 mg/day vs. placebo
(Calcium 1000 mg/day and if 25-hydroxyvitamin level was < 40 nmol/L, they received vitamin D 500
IU/day)
Outcomes Hip Fractures: Radiographically confirmed.
Non-vertebral Fractures: Radiographically confirmed osteoporotic fractures of wrist leg, humerus, hip,
pelvis or clavicle
Notes
Risk of bias
Item Authors’ judgement Description
44Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
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McClung 2001 (Continued)
Allocation concealment? Unclear B - Unclear
Mortensen 1998
Methods Randomized controlled trial
Primary prevention
Blinding: double blind, identical placebo
Study length: 2
on drug plus 3rd year drug free follow up. (Patients given option to continue in study after completing
1st year.)
Withdrawals:
Continuous: 20/37 (54.1%)
Cyclic: 14/38 (36.8%)
Placebo: 15/36 (41.7%)
Total:49/111 (44%)
Participants Source: Two centres - USA and Denmark
Inclusion Criteria: Ambulatory, active women 6-60 month postmenopausal (as measured by FSH and
estradiol) weighing 45-90 kg (within 25% of normal height and weight). Lumbar spine within 2 SD of
age matched bone mass
Exclusion Criteria: Bisphosphonates, thyroid hormone therapy, glucocorticoids = 5 mg/day, anabolic
agents, calcitonin, vitamin D > 400 IU/day, calcium > 1500/day, diuretics, anticonvulsants > 1 month
in previous 6 months, HRT > 1 month in previous 6 months, fluoride > 1 month ever, any bone disease
including hyperparathyroidism, alcohol or drug abuse, psychiatric disease, any evidence of osteoporosis
- vertebral deformity or osteoporosis related fracture of hip or wrist, bilateral oophorectomy, or artificial
menopause.
Note: Nothing in criteria to indicate exclusion of those with upper GI disease.
Treatment N: 37, 38
Control N: 36
Age: 51.2 (3.8); YSM: 2.7 (1.7)
Calcium: 977 (535)mg/d
BMD: 0.94 (0.11) g/cm2
T-score: -1.0
Fractures: 0% (excluded)
Interventions Risedronate 5 mg/day or cyclical risedronate 5 mg/day for 1st 2 wk of every calendar month followed by
placebo for remainder vs. placebo
(Not required to take supplemental calcium.)
Outcomes Vertebral fractures - Thoracic and lumbar radiographs were taken at baseline, 7, 13 and 25 months and
12 months after treatment cessation. Vertebral deformities were defined as a 25% or more decrease in
anterior, mid or posterior, height of a vertebra as compared to baseline and were evaluated for safety
purposes
Non-vertebral fractures- Ascertainment not specified but adverse events were recorded at all patient visits.
This endpoint was not included in the meta-analysis as the evaluation period appeared to include the
follow up time in which patients were off drug
Notes
45Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
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Mortensen 1998 (Continued)
Risk of bias
Item Authors’ judgement Description
Allocation concealment? Unclear B - Unclear
Reginster 2000
Methods Randomized controlled trial
Secondary prevention
Blinding: double blind unspecified
Study length: 3
(2.5 mg/dose discontinued at 2 years due to protocol amendment)
Withdrawals:
2.5 mg (at 1 year): 76/408 (18.6%)
5.0 mg (at 3 years): 156/407 (38.3%)
Placebo (at 3 years): 186/407 (45.7%)
Total for 5.0 mg and placebo: 342/814 (40%)
Participants Source: 80 European and Australian centres. VERT study.
Inclusion Criteria: Ambulatory women up to 85 years old who had been post menopausal at least 5 years.
Minimum two radiographically confirmed vertebral T4-L4 fractures
Exclusion Criteria: Conditions that could interfere with evaluation of spinal osteoporosis, calcitonin,
calcitriol or Vitamin D within one month, anabolic steroids, or HRT within 3 months, bisphosphonates,
fluoride within 6 months.
Note: Patients with previous or ongoing upper GI disease or use of medications associated with GI
intolerance (NSAIDS or asprin) were not excluded
Treatment N: 408, 407
Control N: 407
Age: 71.0 (7.0); YSM: 24.4 (8.5)
Calcium: not reported
BMD: 0.79 g/cm2 (0.15)
T-score: -2.7
Fractures: 100%
Interventions Risedronate 2.5 mg/day or risedronate 5 mg/day vs. placebo
(Calcium 1000 mg/day and if 25-hydroxyvitamin level was < 40 nmol/l, they received vitamin D 500
IU/day)
Outcomes Primary Outcome: Vertebral fractures
Vertebral Fractures: Lateral thoracolumbar T4-L4 spine radiographs were obtained at baseline, 1,2 and 3
years and were read in the order they were taken at a single radiology department. Prevalent and incident
fractures were diagnosed quantitatively and semi-quantitatively. Quantitative assessment defined incident
fracture as a 15% decrease of anterior, posterior or middle vertebral height in a vertebra that was normal
at baseline. In the semiquantitative assessment a new fracture was diagnosed if the grade changed from
0 (normal) to 1(mild) 2 (moderate), or 3 (severe). An independent radiologist adjudicated discrepancies
between methods
Non-vertebral Fractures: Radiographically confirmed fractures of the clavicle, humerus, wrist, pelvis, hip
46Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
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Reginster 2000 (Continued)
or leg, regardless of relationship to trauma
Notes
Risk of bias
Item Authors’ judgement Description
Allocation concealment? Unclear B - Unclear
BMD: Lumbar Bone Mineral Density
Calcium: Baseline calcium intake
GI: gastointestinal
HRT: hormone replacement therapy
NSAID: Non steroidal anti inflammatory drugs
Participant Characteristics: Unless othewise specified, participant characteristics are presented as mean (SD)
SD: Standard deviation
t-score calculated using the lumbar spine BMD [(LS BMD -1.047)/0.110]
vs: versus
YSM: Years Since Menopause
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Brown 2002 Lack of an appropriate control group.
Delmas 1997 Lack of fracture outcome.
Dobnig 2006 Lack of fracture outcome.
Eastell 2003 Duplicate report or earlier report of another study.
Eriksen 2002 Lack of fracture outcome.
Goa 1998 Non randomized.
Harris 1999b Lack of an appropriate control group.
Harris 2001 Lack of an appropriate control group.
Hooper 1999 Lack of fracture outcome.
Hosking 2003 Lack of appropriate fracture data (i.e. reported as adverse event and unspecified.)
47Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
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(Continued)
Hu 2005 Lack of fracture outcome.
Kushida 2004 Lack of an appropriate control group.
Leung 2005 Lack of fracture outcome.
Li 2005 Lack of fracture outcome.
Licata 1997 Non randomized.
McClung 1998 1 No extractable data.
Miller 1999 Duplicate report or earlier report of another study.
Reginster 2001 Duplicate report or earlier report of another study.
Reszka 1999 Non randomized.
Ribot 1999 Duplicate report or earlier report of another study.
Roux 2004 Duplicate report or earlier report of another study.
Singer 1995 Non randomized.
Sorensen 2003 Extension / discontinuation study.
Ste-Marie 2004 Extension study.
Watts 1998 Non randomized.
Watts 1999 Duplicate report or earlier report of another study.
Watts 2003 Duplicate report or earlier report of another study.
Yildirim 2005 Lack of fracture outcome.
Zegels 2001 Duration of therapy < 1 year.
48Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
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D A T A A N D A N A L Y S E S
Comparison 1. Risedronate 5 mg vs Control - all years baseline denominators
Outcome or subgroup titleNo. of
studies
No. of
participants Statistical method Effect size
1 Vertebral Fractures 5 3139 Risk Ratio (M-H, Fixed, 95% CI) 0.63 [0.51, 0.77]
1.1 Vertebral Primary 2 327 Risk Ratio (M-H, Fixed, 95% CI) 0.97 [0.42, 2.25]
1.2 Vertebral secondary 3 2812 Risk Ratio (M-H, Fixed, 95% CI) 0.61 [0.50, 0.76]
Comparison 2. Risedronate 5 mg vs Control - all years baseline denominators
Outcome or subgroup titleNo. of
studies
No. of
participants Statistical method Effect size
1 Non Vertebral Fractures 5 12397 Risk Ratio (M-H, Fixed, 95% CI) 0.80 [0.72, 0.90]
1.1 Non Vertebral Primary 1 254 Risk Ratio (M-H, Fixed, 95% CI) 0.81 [0.25, 2.58]
1.2 Non vertebral secondary 4 12143 Risk Ratio (M-H, Fixed, 95% CI) 0.80 [0.72, 0.90]
Comparison 3. Risedronate 5 mg vs Control - all years baseline denominators
Outcome or subgroup titleNo. of
studies
No. of
participants Statistical method Effect size
1 Hip Fractures 4 11859 Risk Ratio (M-H, Fixed, 95% CI) 0.74 [0.59, 0.94]
1.1 Hip primary 1 73 Risk Ratio (M-H, Fixed, 95% CI) Not estimable
1.2 Hip secondary 3 11786 Risk Ratio (M-H, Fixed, 95% CI) 0.74 [0.59, 0.94]
Comparison 4. Risedronate 5 mg vs Control - all years baseline denominators
Outcome or subgroup titleNo. of
studies
No. of
participants Statistical method Effect size
1 Wrist Fractures 3 2528 Risk Ratio (M-H, Fixed, 95% CI) 0.67 [0.42, 1.07]
1.1 Wrist primary 1 73 Risk Ratio (M-H, Fixed, 95% CI) Not estimable
1.2 Wrist secondary 2 2455 Risk Ratio (M-H, Fixed, 95% CI) 0.67 [0.42, 1.07]
49Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
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Comparison 5. Risedronate 5 mg vs Control - 1 year baseline denominators
Outcome or subgroup titleNo. of
studies
No. of
participants Statistical method Effect size
1 Fractures 3 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
1.1 Vertebral primary 1 73 Risk Ratio (M-H, Fixed, 95% CI) Not estimable
1.2 Vertebral secondary 2 2455 Risk Ratio (M-H, Fixed, 95% CI) 0.40 [0.27, 0.59]
1.3 Hip primary 1 73 Risk Ratio (M-H, Fixed, 95% CI) Not estimable
1.4 Wrist primary 1 73 Risk Ratio (M-H, Fixed, 95% CI) Not estimable
Comparison 6. Risedronate 5 mg vs Control - 2 years baseline denominators
Outcome or subgroup titleNo. of
studies
No. of
participants Statistical method Effect size
1 Fractures 3 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
1.1 Vertebral primary 2 327 Risk Ratio (M-H, Fixed, 95% CI) 0.97 [0.42, 2.25]
1.2 Vertebral secondary 1 357 Risk Ratio (M-H, Fixed, 95% CI) 0.48 [0.21, 1.08]
1.3 Non vertebral primary 1 254 Risk Ratio (M-H, Fixed, 95% CI) 0.81 [0.25, 2.58]
1.4 Non vertebral secondary 1 357 Risk Ratio (M-H, Fixed, 95% CI) 0.55 [0.22, 1.34]
1.5 Hip primary 1 73 Risk Ratio (M-H, Fixed, 95% CI) Not estimable
1.6 Wrist secondary 1 73 Risk Ratio (M-H, Fixed, 95% CI) Not estimable
Comparison 7. Risedronate 5 mg vs Control - 2 years baseline denominators
Outcome or subgroup titleNo. of
studies
No. of
participants Statistical method Effect size
1 Fractures 3 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
1.1 Vertebral 3 684 Risk Ratio (M-H, Fixed, 95% CI) 0.66 [0.37, 1.18]
1.2 Non vertebral 2 611 Risk Ratio (M-H, Fixed, 95% CI) 0.63 [0.31, 1.28]
1.3 Hip 1 73 Risk Ratio (M-H, Fixed, 95% CI) Not estimable
1.4 Wrist 1 73 Risk Ratio (M-H, Fixed, 95% CI) Not estimable
50Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
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Comparison 8. Risedronate 5 mg vs Control - 3 years baseline denominators
Outcome or subgroup titleNo. of
studies
No. of
participants Statistical method Effect size
1 Fractures 3 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
1.1 Vertebral secondary 2 2455 Risk Ratio (M-H, Fixed, 95% CI) 0.63 [0.50, 0.78]
1.2 Non vertebral secondary 3 11786 Risk Ratio (M-H, Fixed, 95% CI) 0.81 [0.72, 0.91]
1.3 Hip secondary 3 11786 Risk Ratio (M-H, Fixed, 95% CI) 0.74 [0.59, 0.94]
1.4 Wrist secondary 2 2455 Risk Ratio (M-H, Fixed, 95% CI) 0.67 [0.42, 1.07]
Comparison 9. Risedronate 2.5 mg vs Control - 1 year baseline denominators
Outcome or subgroup titleNo. of
studies
No. of
participants Statistical method Effect size
1 Fractures 2 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
1.1 Vertebral 2 2452 Risk Ratio (M-H, Fixed, 95% CI) 0.54 [0.38, 0.76]
Comparison 10. Risedronate 2.5 mg vs Control - 2 years baseline denominators
Outcome or subgroup titleNo. of
studies
No. of
participants Statistical method Effect size
1 Fractures 2 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
1.1 Vertebral 2 540 Risk Ratio (M-H, Fixed, 95% CI) 0.92 [0.52, 1.62]
1.2 Non vertebral 2 540 Risk Ratio (M-H, Fixed, 95% CI) 0.50 [0.21, 1.19]
Comparison 11. Risedronate 2.5 mg vs Control - 2 years baseline denominators
Outcome or subgroup titleNo. of
studies
No. of
participants Statistical method Effect size
1 Fractures 2 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
1.1 Vertebral primary 1 252 Risk Ratio (M-H, Fixed, 95% CI) 1.08 [0.48, 2.46]
1.2 Vertebral secondary 1 288 Risk Ratio (M-H, Fixed, 95% CI) 0.78 [0.35, 1.76]
1.3 Non vertebral primary 1 252 Risk Ratio (M-H, Fixed, 95% CI) 0.49 [0.13, 1.92]
1.4 Non vertebral secondary 1 288 Risk Ratio (M-H, Fixed, 95% CI) 0.51 [0.17, 1.53]
51Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Comparison 12. Risedronate 2.5 mg vs Control - all years baseline denominators
Outcome or subgroup titleNo. of
studies
No. of
participants Statistical method Effect size
1 Vertebral fractures 4 2992 Risk Ratio (M-H, Fixed, 95% CI) 0.62 [0.46, 0.83]
1.1 Primary prevention 1 252 Risk Ratio (M-H, Fixed, 95% CI) 1.08 [0.48, 2.46]
1.2 Secondary prevention 3 2740 Risk Ratio (M-H, Fixed, 95% CI) 0.57 [0.42, 0.78]
2 Non-vertebral fractures 2 540 Risk Ratio (M-H, Fixed, 95% CI) 0.50 [0.21, 1.19]
2.1 Primary prevention 1 252 Risk Ratio (M-H, Fixed, 95% CI) 0.49 [0.13, 1.92]
2.2 Secondary prevention 1 288 Risk Ratio (M-H, Fixed, 95% CI) 0.51 [0.17, 1.53]
Comparison 13. Risedronate 5 mg vs Control - all years baseline denominators
Outcome or subgroup titleNo. of
studies
No. of
participants Statistical method Effect size
1 Withdrawals due to side effects 5 9204 Risk Ratio (M-H, Fixed, 95% CI) 0.96 [0.88, 1.05]
2 Withdrawals overall 6 12486 Risk Ratio (M-H, Fixed, 95% CI) 0.96 [0.91, 1.00]
A D D I T I O N A L T A B L E S
Table 1. Clinical Relevance Table for Fracture Primary Prevention Trials
Outcome # Patients #
Trials
Control
Event Rate
Wt Absolute
RD
Wt Rel %
Change
NNTB Statistical Sig Quality of
Evidence
Verte-
bral Fractures
- (Trial Popu-
lation) Pri-
mary Preven-
tion 5mg/day
for 2 yrs
327 (2) 6.2% (6 out of
100)
0% 0 fewer
patients out of
100
-3% (I) Not applicable Not Statis-
tically signifi-
cant
Silver
95% confi-
dence interval
(-5, 5) (-58, 125)
Verte-
bral Fractures
- (Low Risk
Woman) Pri-
mary Preven-
tion 5mg/day
for 2 years
327 (2) 1.2% (1 out of
100)
Not applicable -3% (I) Not applicable Not Statis-
tically signifi-
cant
Silver
52Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
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Table 1. Clinical Relevance Table for Fracture Primary Prevention Trials (Continued)
95% confi-
dence interval
(-58, 125)
Verte-
bral Fractures
- (Moderate
Risk Woman)
Primary Pre-
vention 5mg/
day for 2 yrs
327 (2) 5.3% (5 out of
100)
Not applicable -3% (I) Not applicable Not Statis-
tically signifi-
cant
Silver
95% confi-
dence interval
(-58, 125)
Non Vertebral
Fractures -
(Trial Popula-
tion) Primary
Prevention
(5 mg/day for
2 yrs)
254 (1) 4.8% (5 out of
100)
-1% 1 fewer
patient out of
100
-19% (I) Not applicable Not Statis-
tically signifi-
cant
Silver
95% confi-
dence interval
(-3, 4) (-75, 158)
Non Vertebral
Fractures
- (Low Risk
Woman) Pri-
mary Preven-
tion(5 mg/day
for 2 yrs)
254 (1) 8.9% (9 out of
100)
Not applicable -19% (I) Not applicable Not Statis-
tically signifi-
cant
Silver
95% confi-
dence interval
(-75, 158)
Non Vertebral
Frac-
tures - (Mod-
erate Risk
Woman) Pri-
mary Preven-
tion(5 mg/day
for 2 yrs)
254 (1) 16.5% (17 out
of 100)
Not applicable -19% (I) Not applicable Not Statis-
tically signifi-
cant
Silver
95% confi-
dence interval
(-75, 158)
53Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Table 1. Clinical Relevance Table for Fracture Primary Prevention Trials (Continued)
Hip Fractures
- (Trial Popu-
lation) Pri-
mary Preven-
tion (5mg/day
for 2 yrs)
73 (1) 0.0 (0 out of
100)
0% 0 fewer
patients out of
100
Not estimable Not applicable Not Statis-
tically signifi-
cant
Silver
95% confi-
dence interval
(-5, 5)
Hip Fractures
- (Low Risk
Woman) Pri-
mary Preven-
tion (5mg/day
for 2 yrs)
73 (1) 0.4% (0 out of
100)
Not applicable Not estimable
(I)
Not applicable Not Statis-
tically signifi-
cant
Silver
95% confi-
dence interval
Hip Fractures
- (Moderate
Risk Woman)
Primary Pre-
vention (5mg/
day for 2 yrs)
73 (1) 1.9% (2 out of
100)
Not applicable Not estimable Not applicable Not Statis-
tically signifi-
cant
Silver
95% confi-
dence interval
Wrist Frac-
tures - (Trial
Population)
Primary Pre-
vention (5mg/
day for 2 yrs)
73 (1) 0% (0 out of
100)
-0% 0 fewer
patients out of
100
Not estimable Not applicable Not statis-
tically signifi-
cant
Silver
95% confi-
dence interval
(-5, 5)
Wrist Frac-
tures - (Low
Risk Woman)
Primary Pre-
vention (5mg/
day for 2 yrs)
73 (1) Not available Not applicable Not estimable Not applicable Not statis-
tically signifi-
cant
Silver
95% confi-
dence interval
54Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
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Table 1. Clinical Relevance Table for Fracture Primary Prevention Trials (Continued)
Wrist Frac-
tures - (Mod-
erate Risk
Woman) Pri-
mary Preven-
tion (5mg/day
for 2 yrs)
73 (1) Not available Not applicable Not estimable Not applicable Not statis-
tically signifi-
cant
Silver
95% confi-
dence interval
Legend Secondary
prevention =
bone density
of at least 2
SD values be-
low peak bone
mass and/
or one or more
vertebral com-
pression frac-
tures
For Trial Pop-
ulation rates
are based on
the event rate
in the control
group. Low
and Mod-
erate Risk, are
5 year com-
munity popu-
lation risks de-
rived from the
following vari-
ables
in the FRAC-
TURE Index:
age,
fracture after
50 yrs, mater-
nal hip frac-
ture after 50
yrs., weight <
125 lbs, smok-
ing, using
arms to assist
standing and
BMD. Low =
FRACTURE
Index score 1-
2, Moderate =
FRAC-
TURE Index
score 5 (Black
2001) see Fig-
ure 1
Wt =
weighted, RD
= risk differ-
ence
Wt Rel
= weighted rel-
ative percent
change, I = im-
provement
NNT
B = number
needed to ben-
efit
Gold level: At
least one ran-
domised clini-
cal trial meets
all of the fol-
lowing criteria
for the major
outcome
(s) as reported:
Sample sizes of
at least 50 per
group. If a sta-
tistically
significant dif-
ference is not
found they
must be pow-
ered for 20%
relative differ-
ence in the rel-
evant out-
come. Blind-
ing of patients
and as-
sessors for out-
comes. Han-
dling of with-
drawals > 80%
follow up (im-
puta-
tions based on
methods such
as Last Obser-
vation Carried
55Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Table 1. Clinical Relevance Table for Fracture Primary Prevention Trials (Continued)
For-
ward (LOCF)
acceptable).
Concealment
of treatment
allocation. Sil-
ver level: Ran-
domised trial
does not meet
the above cri-
teria
Table 2. Clinical Relevance Table for Fracture Secondary Prevention Trials
Outcome # Patients #
Trials
Control
Event Rate
Wt Absolute
RD
Wt Rel %
Change
NNTB Statistical Sig Quality of
Evidence
Verte-
bral Fractures
- (Trial Pop-
ulation) Sec-
ondary Pre-
vention 5 mg/
day for 3 yrs
2,812 (3) 14.1% (14 out
of 100)
-5% 5 fewer
patients out of
100
-39% (I) 19 Statistically
significant
Gold
95% confi-
dence interval
(-8, -3) (-50, -24) (15, 30)
Verte-
bral Fractures
- (Moderate
Risk Woman)
Secondary
Prevention 5
mg/day for 3
years
2,812 (3) 5.3% (5 out of
100)
Not applicable -39% (I) 49 Statistically
significant
Gold
95% confi-
dence interval
(-50, -24) (38, 79)
Verte-
bral Fractures
- (High Risk
Woman) Sec-
ondary Pre-
vention 5 mg/
day for 3 yrs
2,812 (3) 11.2% (11 out
of 100)
Not applicable -39% (I) 23 Statistically
significant
Gold
56Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
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Table 2. Clinical Relevance Table for Fracture Secondary Prevention Trials (Continued)
95% confi-
dence interval
(-50, -24) (18, 38)
Non Vertebral
Fractures
- (Trial Pop-
ulation) Sec-
ondary Pre-
vention(5 mg/
day for 2-3
yrs)
12,143 (4) 10.3% (10 out
of 100)
-2% 2 fewer
patients out of
100
-20% (I) 49 Statistically
significant
Gold
95% confi-
dence interval
(-3, -1) (-28, -10) (35, 98)
Non Vertebral
Frac-
tures - (Mod-
erate Risk
Woman) Sec-
ondary Pre-
vention(5 mg/
day for 2-3
yrs)
12,143 (4) 16.5% (17 out
of 100)
Not applicable -20% (I) 31 Statistically
significant
Gold
95% confi-
dence interval
(-28, -10) (22, 61)
Non Vertebral
Fractures
- (High Risk
Woman) Sec-
ondary Pre-
vention(5 mg/
day for 2-3
yrs)
12,143 (4) 27.5% (28 out
of 100)
Not applicable -20% (I) 19 Statistically
significant
Gold
95% confi-
dence interval
(-28, -10) (13, 37)
Hip Fractures
- (Trial Pop-
ulation) Sec-
ondary
Prevention (5
mg/day for 3
yrs)
11,786 (3) 2.8 (3 out of
100)
-1% 1 fewer
patient out of
100
-26% (I) 138 Statistically
significant
Silver
57Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
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Table 2. Clinical Relevance Table for Fracture Secondary Prevention Trials (Continued)
95% confi-
dence interval
(-1, 0) (-41, -6) (88, 596)
Hip Fractures
- (Moderate
Risk Woman)
Secondary
Prevention (5
mg/day for 3
yrs)
11,786 (3) 1.9% (2 out of
100)
Not applicable -26% (I) 203 Statistically
significant
Silver
95% confi-
dence interval
(-41, -6) (129, 878)
Hip Fractures
- (High Risk
Woman) Sec-
ondary
Prevention (5
mg/day for 3
yrs)
11,786 (3) 8.7% (9 out of
100)
Not applicable -26% (I) 45 Statistically
significant
Silver
95% confi-
dence interval
(-41, -6) (29, 192)
Wrist Frac-
tures - (Trial
Population)
Secondary
Prevention (5
mg/day for 3
yrs)
2,455 (2) 3.5% (4 out of
100)
-1% 1 fewer
patient out of
100
-33% (I) Not applicable Not statis-
tically signifi-
cant
Silver
95% confi-
dence interval
(-2, 0) (-58, 7)
Wrist Frac-
tures - (Mod-
erate
Risk Woman)
Secondary
Prevention (5
mg/day for 3
yrs)
2,455 (2) Not available Not applicable -33% (I) Not applicable Not statis-
tically signifi-
cant
Silver
95% confi-
dence interval
(-58, 7) (I)
58Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
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Table 2. Clinical Relevance Table for Fracture Secondary Prevention Trials (Continued)
Wrist Frac-
tures - (High
Risk Woman)
Secondary
Prevention (5
mg/day for 3
yrs)
2,455 (2) Not available Not applicable -33% (I) Not applicable Not statis-
tically signifi-
cant
Silver
95% confi-
dence interval
(-58, 7)
Legend Secondary
prevention =
bone density
of at least 2
SD values be-
low peak bone
mass and/
or one or more
vertebral com-
pression frac-
tures
For Trial Pop-
ulation
rates are based
on the event
rate in the
control group.
Moderate and
High Risk, are
5 year com-
munity popu-
lation risks de-
rived from the
following vari-
ables
in the FRAC-
TURE Index:
age,
fracture after
50 yrs, mater-
nal hip frac-
ture after 50
yrs, weight <
125 lbs, smok-
ing, using
arms to assist
standing and
BMD. Mod-
erate = FRAC-
TURE Index
score
3-4, High =
FRACTURE
Index score 8-
13 (Black
2001) see Fig-
ure 1
Wt =
weighted, RD
= risk differ-
ence
Wt Rel
= weighted rel-
ative percent
change, I = im-
provement
NNT
B = number
needed to ben-
efit
Gold level: At
least one ran-
domised clini-
cal trial meets
all of the fol-
lowing criteria
for the major
outcome
(s) as reported:
Sample sizes of
at least 50 per
group. If a sta-
tistically
significant dif-
ference is not
found they
must be pow-
ered for 20%
relative differ-
ence in the rel-
evant out-
come. Blind-
ing of patients
and as-
sessors for out-
comes. Han-
dling of with-
drawals > 80%
follow up (im-
puta-
tions based on
methods such
as Last Obser-
vation Carried
59Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Table 2. Clinical Relevance Table for Fracture Secondary Prevention Trials (Continued)
For-
ward (LOCF)
acceptable).
Concealment
of treatment
allocation. Sil-
ver level: Ran-
domised trial
does not meet
the above cri-
teria
W H A T ’ S N E W
Last assessed as up-to-date: 13 November 2007.
Date Event Description
13 August 2008 Amended Absolute event rates included in the Plain language summary
28 May 2008 Amended Converted to new review format. CMSG ID C072-R
H I S T O R Y
Review first published: Issue 4, 2003
Date Event Description
14 November 2007 New citation required and conclusions have changed See published notes for details on update.
60Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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C O N T R I B U T I O N S O F A U T H O R S
George Wells was involved in the conception, design and implementation of the project and contributed significantly to the writing of
the report.
Ann Cranney was involved with the conception of the review, data abstraction, analysis, interpretation and revision of the final report.
Joan Peterson screened the literature, was involved in the data abstraction, quality assessment and analysis of the primary trials and
contributed significantly to the writing of the report.
Michel Boucher assisted in the design of the analysis, reporting and interpretation of the findings and was involved in the writing of
the report.
Beverley Shea was involved in developing the protocol and conducting the systematic review.
Vivian Robinson was involved in developing the protocol and conducting the systematic review.
Douglas Coyle assisted with the design of the review and reviewed the analysis.
Peter Tugwell provided clinical rheumatology expertise and methodological guidance.
D E C L A R A T I O N S O F I N T E R E S T
None at present.
The Cochrane Funding Arbitration Panel recommended withdrawal of the original review from The Cochrane Library. The original
review was externally supported by Merck and Proctor & Gamble to support research staff.
This current review was updated without the support of any industry sponsor.
S O U R C E S O F S U P P O R T
Internal sources
• Ottawa Health Research Institute, Canada.
External sources
• Canadian Agency for Drugs and Technologies in Health, Canada.
N O T E S
This review updated a previously published review (Cranney 2003) of risedronate conceived, conducted and completed, in part, by the
authors of this report. There were four general differences in the manner in which the two reviews were conducted. First, the current
review included articles published after the previous review was completed (updated to Feb 2007). Second, although both published
and unpublished data were used in the previous reviews, only published data were used in this review. Third, in the previous review the
random-effects model was always used whereas in the present review the base analysis used the fixed-effect model unless the results were
heterogeneous. Fourth, although the previous review considered both BMD and fracture data, this review was only concerned with
fractures and therefore the definition of primary and secondary prevention put more of an emphasis on the fracture study inclusion
criteria.
Our updated literature search retrieved an additional trial (Hooper 2005) which was published after the previous review. There were
two changes in the choice of the included trials. First, the trials by Mortensen (Mortensen 1998) at 5 mg per day (for non-vertebral
fracture data) and Clemmesen (Clemmesen 1997) at 2.5 mg per day (for vertebral and non-vertebral fracture data) were included
in the previous review but were excluded for the current review since they appeared to include an off drug treatment period. That
61Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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is, the fractures may have occurred during the follow-up period on no treatment and not during the active treatment phase of the
study. Second, in the previous review, additional data were obtained from the authors for the McClung trial (McClung 2001) but this
additional information was not used in the current review.
I N D E X T E R M S
Medical Subject Headings (MeSH)
Bone Density Conservation Agents [adverse effects; ∗therapeutic use]; Etidronic Acid [adverse effects; ∗analogs & derivatives; therapeutic
use]; Fractures, Bone [∗prevention & control]; Hip Fractures [prevention & control]; Osteoporosis, Postmenopausal [∗drug therapy;
prevention & control]; Randomized Controlled Trials as Topic; Spinal Fractures [prevention & control]
MeSH check words
Female; Humans
62Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Strontium ranelate for preventing and treating
postmenopausal osteoporosis (Review)
O’Donnell S, Cranney A, Wells GA, Adachi JD, Reginster JY
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library2006, Issue 3
http://www.thecochranelibrary.com
1Strontium ranelate for preventing and treating postmenopausal osteoporosis (Review)
Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
INTERNAL U
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T A B L E O F C O N T E N T S
1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4CRITERIA FOR CONSIDERING STUDIES FOR THIS REVIEW . . . . . . . . . . . . . . . . . .
5SEARCH METHODS FOR IDENTIFICATION OF STUDIES . . . . . . . . . . . . . . . . . . .
5METHODS OF THE REVIEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6DESCRIPTION OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7METHODOLOGICAL QUALITY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12POTENTIAL CONFLICT OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . .
12ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
15TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
15Characteristics of included studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
16Characteristics of excluded studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
17ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
17Table 01. Clinical relevance table strontium ranelate 2 g per day: Fractures & safety data . . . . . . . . . .
18Table 02. Clinical relevance table strontium ranelate 2 g per day: BMD data . . . . . . . . . . . . . .
18Table 03. Other adverse events from additional sources (EMEA 2004* and Servier**) . . . . . . . . . . .
19ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
19Comparison 01. Fractures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
19Comparison 02. BMD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
19Comparison 03. Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
19COVER SHEET . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
21GRAPHS AND OTHER TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
21Analysis 01.01. Comparison 01 Fractures, Outcome 01 Verterbral fractures . . . . . . . . . . . . . . .
21Analysis 01.02. Comparison 01 Fractures, Outcome 02 Non-vertebral fractures . . . . . . . . . . . . .
22Analysis 02.01. Comparison 02 BMD, Outcome 01 Lumbar spine BMD not adjusted for strontium content . . .
23Analysis 02.02. Comparison 02 BMD, Outcome 02 Lumbar spine adjusted for strontium content . . . . . . .
24Analysis 02.03. Comparison 02 BMD, Outcome 03 Femoral neck . . . . . . . . . . . . . . . . . .
25Analysis 02.04. Comparison 02 BMD, Outcome 04 Total hip . . . . . . . . . . . . . . . . . . .
25Analysis 03.01. Comparison 03 Adverse Events, Outcome 01 Total withdrawls . . . . . . . . . . . . .
26Analysis 03.02. Comparison 03 Adverse Events, Outcome 02 Withdrawals due to adverse events . . . . . . .
27Analysis 03.03. Comparison 03 Adverse Events, Outcome 03 Number of emergent adverse events . . . . . . .
28Analysis 03.04. Comparison 03 Adverse Events, Outcome 04 Serious adverse events . . . . . . . . . . . .
28Analysis 03.05. Comparison 03 Adverse Events, Outcome 05 Diarrhea . . . . . . . . . . . . . . . .
29Analysis 03.06. Comparison 03 Adverse Events, Outcome 06 Gastritis . . . . . . . . . . . . . . . .
29Analysis 03.07. Comparison 03 Adverse Events, Outcome 07 Deaths . . . . . . . . . . . . . . . . .
iStrontium ranelate for preventing and treating postmenopausal osteoporosis (Review)
Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
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Strontium ranelate for preventing and treatingpostmenopausal osteoporosis (Review)
O’Donnell S, Cranney A, Wells GA, Adachi JD, Reginster JY
Status: New
This record should be cited as:
O’Donnell S, Cranney A, Wells GA, Adachi JD, Reginster JY. Strontium ranelate for preventing and treating postmenopausal osteo-
porosis. Cochrane Database of Systematic Reviews 2006, Issue 3. Art. No.: CD005326. DOI: 10.1002/14651858.CD005326.pub2.
This version first published online: 19 July 2006 in Issue 3, 2006.
Date of most recent substantive amendment: 24 May 2006
A B S T R A C T
Background
Strontium ranelate is a new anti-osteoporosis therapy therefore, its benefits and harms need to be known.
Objectives
To determine the efficacy and safety of strontium ranelate for the treatment and prevention of postmenopausal osteoporosis.
Search strategy
We searched MEDLINE (1996 to March 2005), EMBASE (1996 to week 9 2005), the Cochrane Library (1996 to Issue 1 2005),
reference lists of relevant articles and conference proceedings from the last two years. Additional data was sought from authors and
industry sponsors.
Selection criteria
We included randomized controlled trials (RCTs) of at least one year duration comparing strontium ranelate versus placebo reporting
fracture incidence, bone mineral density (BMD), health related quality of life and/or safety outcomes in postmenopausal women.
Treatment (versus prevention) population was defined as women with prevalent vertebral fractures and/or lumbar spine BMD T score
< -2.5 SD.
Data collection and analysis
Two reviewers independently determined study eligibility, assessed trial quality and extracted the relevant data. Disagreements were
resolved by consensus. RCTs were grouped by dose of strontium ranelate and treatment duration. Where possible, meta-analysis was
conducted using the random effects model.
Main results
A total of four trials met our inclusion criteria, three of which investigated the effects of strontium ranelate compared to placebo in
a treatment population (doses ranged from 0.5 to 2 g daily) and one, in a prevention population (doses 0.125, 0.5 and 1 g daily). In
osteoporotic, postmenopausal women a 37% reduction in vertebral fractures (two trials, n = 5082, RR 0.63, 95% CI 0.56 to 0.71)
and a 14% reduction in non-vertebral fractures (two trials, n = 6572, RR 0.86, 95% CI 0.75 to 0.98) was demonstrated over a three
year period with 2 g of strontium ranelate daily. An increase in BMD at all sites was shown with the same dose: lumbar spine BMD
(two trials, n = 1614, WMD adjusted for strontium content 5.44, 95% CI 3.41 to 7.46 and WMD not adjusted 11.29, 95% CI 10.22
to 12.37 over two years), femoral neck and total hip (two trials, n = 4230, WMD 8.25, 95% CI 7.84 to 8.66 and WMD 9.83, 95%
CI 9.39 to 10.26 respectively over three years). One gram of strontium ranelate daily in postmenopausal women without osteoporosis
increased BMD at all sites over a two year period: lumbar spine (one trial, n = 59, WMD adjusted for strontium content 2.39, 95%
CI 0.15 to 4.63 and WMD not adjusted 6.68, 95% CI 5.16 to 8.20), femoral neck (one trial, n= 60, WMD 2.52, 95%CI 0.96 to
4.09) and total hip (one trial, n = 60, WMD 1.02, 95% CI 0.48 to 1.56). In both the treatment and prevention populations, lower
doses of strontium ranelate were superior to placebo with the highest dose of strontium ranelate demonstrating the greatest reduction
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in vertebral fractures and increase in BMD. There is some evidence to suggest that 2 g of strontium ranelate daily compared to placebo
may have a beneficial effect on health related quality of life in postmenopausal women after three years of treatment. Two grams of
strontium ranelate daily increased the risk of diarrhea (RR 1.38%, 95% CI 1.02 to 1.87); however, adverse events did not affect the
risk of discontinuing strontium ranelate nor did it increase the risk of serious side effects, gastritis or death. Additional data obtained
suggests that the risk of vascular system disorders including venous thromboembolism (two trials, n = 6669, 2.2% versus 1.5%, OR
1.5, 95% CI 1.1 to 2.1) and pulmonary embolism (two trials, n = 6669, 0.8% versus 0.4%, OR 1.7, 95% CI 1.0 to 3.1) as well as
nervous system disorders such as headaches (3.9% versus 2.9%), seizures (0.3% versus 0.1%), memory loss (2.4% versus 1.9%) and
disturbance in consciousness (2.5% versus 2.0%) is slightly increased with taking 2 g of strontium ranelate daily over a 3 to 4 year
period.
Authors’ conclusions
There is silver level evidence to support the efficacy of strontium ranelate for the reduction of vertebral fractures (and to a lesser extent
non-vertebral fractures) in postmenopausal osteoporotic women and an increase in BMD (all sites) in postmenopausal women with
and without osteoporosis. Diarrhea may occur however, adverse events leading to study withdrawal were not significantly increased in
the strontium ranelate group. Potential risks to the vascular and neurological system associated with taking 2 g of strontium ranelate
daily need to be further explored and quantified.
P L A I N L A N G U A G E S U M M A R Y
Strontium ranelate for osteoporosis in women after menopause
This summary of a Cochrane review presents what we know from research about the effect of strontium ranelate for osteoporosis in
women after menopause. The review shows that:
There is silver level evidence that for treatment of osteoporosis in women after menopause, 2 g of strontium ranelate daily over 3 years
decreases fractures in the spine and slightly decreases fractures not in the spine. Most women do not have side effects that would cause
them to stop taking strontium ranelate. However, other research shows that harms could include a chance of blood clots and seizures,
memory loss and consciousness.
What is osteoporosis and how can strontium ranelate help?
Osteoporosis is a condition in which bone loss occurs. Bone loss leads to weak brittle bones that can break easily, even during everyday
activities. Breaks (fractures) of the spine or non-spine (e.g. wrist and hip) are the most common type. There are many drugs and
minerals that work to treat osteoporosis. Strontium ranelate is a drug that decreases the chance of fractures by slowing the loss of bone
and possibly by building new bone. It is a new drug and therefore its benefits and harms need to be known.
What are the results of this review?
Women in the studies took 2 g of strontium ranelate or a placebo (fake tablets or powder). After 2 to 3 years, the number of fractures
that occurred and bone mineral density was measured. Bone mineral density is a lab test to measure how dense or strong bones are in
the hip, spine or neck. The higher the bone density the better.
Benefits of strontium ranelate
In women after menopause who have osteoporosis:
• strontium ranelate decreases spine fractures
-13 out of 100 women had spine fractures taking strontium ranelate
-21 out of 100 women had spine fractures taking a placebo
• strontium ranelate may decrease fractures that are not in the spine
-11 out of 100 women had non-spine fractures taking strontium ranelate
-13 out of 100 women had non-spine fractures taking a placebo
• strontium ranelate increases bone mineral density
Harms of strontium ranelate
In women after menopause who have osteoporosis:
• strontium ranelate did not cause side effects that would make them stop taking it
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• strontium ranelate did not lead to serious side effects, stomach infections, back pain or death
• strontium ranelate increased diarrhea
-7 out of 100 women had diarrhea taking strontium ranelate
-5 out of 100 women had diarrhea taking a placebo
Other research shows that harms could include a chance of blood clots, and seizures, memory loss and consciousness. The cause of
these neurological side effects are not known.
This review has several limitations which include difficulty interpreting the change in bone mineral density due to the unique aspects
of strontium in bone and incomplete follow-up of some patients within the individual trials.
B A C K G R O U N D
Osteoporosis is a skeletal disorder characterized by low bone mass
and micro-architectural deterioration of bone resulting in an in-
crease in bone fragility and risk of fracture (1993 Consensus; NIH
2001). It most often affects postmenopausal women as reductions
in circulating levels of estrogen lead to accelerated bone turnover
and resorption. The most common sites of osteoporotic fracture
are the wrist, hip and spine however, osteoporotic fractures do oc-
cur at other sites (Seeley 1991). Osteoporotic fractures are a major
burden for the individual, their families and society (Johnell 2004;
Kanis 2003; Cauley 2000). Individuals who suffer osteoporotic
fractures, particularly spine or hip, must deal with the complica-
tions which include reductions in health-related quality-adjusted
life years, increased morbidity and mortality (Cauley 2000; Johnell
2004; Tosteson 2001). Furthermore, the direct and indirect ex-
penditures associated with the care of these individuals, particu-
larly hip fracture patients, is costly (US Dept Health 2004; Ray
1997). In Europe, the number of osteoporotic fractures was esti-
mated to be 3.79 million in 2000 and the associated total direct
costs were 31.7 billion Euros (Kanis 2004). In the United States,
approximately 1.5 million osteoporotic fractures occur each year
(US Dept Health 2004) and the cost of fractures was estimated
to be 20 billion US dollars in 1995 (Ray 1997). With the aging
of the population, and the age-specific increases in osteoporotic
fracture rates, it has been suggested that these costs will more than
double in the coming decades (Burge 2003).
The bone fragility which characterizes this disease is a result of
an imbalance in bone remodeling (bone resorption exceeds bone
formation) and an increase in the rate of remodeling at the tissue
level (Seeman 2002). Risk factors associated with fragility fracture
include advancing age, prior fragility fracture, family history of os-
teoporosis/fracture and low bone mineral density (BMD) (Brown
2002). A working group of the World Health Organization in
1994 proposed that an individual with a BMD more than 2.5
standard deviations (SD) below the young adult mean has osteo-
porosis (WHO 1994). Furthermore, it has been estimated that for
every one SD reduction of BMD, there is an increase in relative
risk of fracture of approximately 1.5 to 2.6 (Marshall 1996).
Effective therapies are available and have been demonstrated to
reduce the relative risk of fracture by 40 to 60% (Cranney 2002).
Pharmacotherapy for prevention and treatment of osteoporosis
includes two primary types of drugs, anti resorptive and anabolic
agents. Anti resorptive agents increase bone strength by decreasing
the number of bone multcellular units. This reduces resporption
and prevents further structural damage of trabecular bone and by
reducing cortical porosity. In contrast, anabolic agents increase
bone strength by increasing bone mass due to an increase in the
number of bone multicellular units. As result the magnitude of
the formation phase is greater than the resorption phase (Riggs
2005).
The majority of the agents currently available for the treatment
of osteoporosis are anti resorptive (e.g. bisphosphonates, estrogen,
selective estrogen modulators and calcitonin) and there are a few
anabolic agents (e.g. intermittent recombinant human parathy-
roid hormone and fluoride) (Sorbera 2003). A novel oral agent,
strontium ranelate, has been suggested to simultaneously decrease
bone resorption and stimulate bone formation although there is
some controversy surrounding its mechanism of action.
Strontium ranelate consists of two divalent cation atoms of sta-
ble strontium (natural element) and an organic moiety (ranelic
acid) which dissociates at the gastro-intestinal level. Strontium is a
cation (i.e. positively charged ion) and physically closely related to
calcium, an active component of the skeleton. Ranelic acid is an
organic, highly polar molecule without pharmacological activity
(EMEA 2004). In vitro, strontium ranelate has been suggested to
have a dual effect on bone however, in vivo long term dosing of
strontium ranelate in OVX rats and monkeys resulted in increased
bone formation but non-significant trends of bone resorption. In
human studies (phase III trials), there is some evidence of increases
in bone formation markers (serum bone-specific alkaline phos-
phatase and C-terminal propeptide of type I procollagen) and de-
creases in markers of bone resorption (serum C-telopeptide and
urinary N-telopeptide cross links) from the third month of treat-
ment (2 g of strontium ranelate daily) up to three years. Poten-
tial mechanisms of action include activation of calcium-sensing
receptor or induction of cellular differentiation. The proposed in-
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dication is for treatment of postmenopausal osteoporosis in order
to reduce the risk of fracture (EMEA 2004).
Different doses of strontium ranelate have been tested. In a two
year randomized controlled trial doses from 0.5 g to 2 g per day
were tested in 353 women with postmenopausal osteoporosis (Me-
unier 2002) and in another two year randomized controlled trial,
doses from 0.125 g to 1 g per day were evaluated in 160 early post-
menopausal women (Reginster 2002-1). In both trials, the pri-
mary efficacy endpoint was BMD and results showed a clear dose
response. All tested doses were superior to placebo with the highest
dose of strontium ranelate (2 g per day) demonstrating the greatest
increase in BMD after adjusting for bone strontium content over
two years (Reginster 2003-1). As a result, 2 g of strontium ranelate
per day is considered the recommended daily dose and was the
only dose evaluated in the two phase III trials (Meunier 2004-1;
Reginster 2005).
Given the potential advantages of strontium ranelate in the pre-
vention and treatment of osteoporosis, and that it is a new ther-
apeutic agent, it is important that the benefits and harms of this
therapy are fully explored through a systematic review of the lit-
erature.
O B J E C T I V E S
To assess the clinical efficacy and safety of strontium ranelate in
the prevention and treatment of osteoporosis compared to placebo
or active comparator in postmenopausal women through a sys-
tematic review of the literature. The following major endpoints
were used for this purpose: 1) Fractures (vertebral and non-ver-
tebral); 2) BMD; 3) Health related quality of life and; 4) Safety.
A treatment (versus prevention) population was defined as post-
menopausal women with prevalent vertebral fractures and/or lum-
bar spine BMD T score < -2.5 SD.
C R I T E R I A F O R C O N S I D E R I N G
S T U D I E S F O R T H I S R E V I E W
Types of studies
Randomized placebo or active comparator-controlled trials of at
least one year duration were included in this review. Studies were
excluded if they were not truly randomized (e.g. patients random-
ized using date of birth) but not on the basis of language of pub-
lication.
Types of participants
Postmenopausal women, in which menopause was either surgically
or naturally induced, were included.
Types of intervention
Trials that investigated the effect of strontium ranelate versus
placebo or an active comparator were included however, trials that
investigated multiple interventions where the effect of strontium
ranelate could not be separated out were not included.
Types of outcome measures
Efficacy measures:
1. The primary efficacy outcome was the number of women with
incident vertebral and non-vertebral fractures (a feasible outcome
for a treatment population). Asymptomatic vertebral fractures
were included if they were either quantitatively or semiquanta-
tively ascertained via a radiographic examination as well, symp-
tomatic (or clinical) vertebral fractures as defined by acute back
pain and radiographical findings were also included. Non-verte-
bral fractures included all appendicular type fractures except frac-
tures of the coccyx, skull, jaw, face, ankle, fingers or toes as they
are not considered to be osteoporotic related (Meunier 2004-1;
Reginster 2005).
2. The secondary efficacy outcome to fractures (or surrogate out-
come) was the mean percent change in BMD of the lumbar spine,
femoral neck and total hip measured by Dual Energy X-Ray Ab-
sorptiometry (DXA) at baseline and yearly intervals (a relevant
outcome for both prevention and treatment populations). Stron-
tium ranelate has a higher atomic number than calcium. When
present in bone as it attenuates x-rays to a greater extent than cal-
cium resulting in an overestimation of BMD as measured by DXA
(Blake 2005). As a result, BMD measurements should be adjusted
for strontium content in order to avoid such an artifactual increase
in BMD. The correction used to adjust for the strontium con-
tent in bone in the lumbar spine BMD measurements has been
described as an indirect method and based on: 1) the correlation
between the strontium content measured in the iliac crest on bone
biopsy and the area under the curve of the integrated strontium
plasma curve; and 2) the correlation between the bone strontium
content measured in lumbar vertebrae and the iliac crest in mon-
keys. However, given that no correlation has been established be-
tween femoral neck and iliac crest bone strontium content is not
adjusted for at the other BMD sites (Meunier 2002).
3. Health Related Quality of Life (a relevant outcome for a treat-
ment population).
4. Safety measures include the following (relevant for both pre-
vention and treatment populations):
i) Total withdrawals (the total number of withdrawals after enrol-
ment in the study).
ii) Withdrawals due to adverse events (withdrawals as a result of
an adverse event)
iii) Number of emergent adverse events (adverse events that de-
veloped during the study).
iv) Serious adverse events (adverse events that were immediately
life-threatening, or resulted in hospitalization, disability, malig-
nant disease or death) (Reginster 2002-1).
v) Number of adverse events affecting the gastrointestinal system
(e.g. diarrhea or gastritis)
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vi) Deaths
S E A R C H M E T H O D S F O R
I D E N T I F I C A T I O N O F S T U D I E S
See: methods used in reviews.
Strontium ranelate is a relatively new drug and it was anticipated
that most of the trials would have been published in the past five
years therefore, our search focused on this time period only. Our
search aimed to identify all trials of strontium ranelate for either
the prevention or treatment of postmenopausal osteoporosis
and we employed the following approaches (based on Cochrane
search strategy outlined by Robinson and Dickersin) (Robinson
2002):
• An electronic search of MEDLINE (1996 to March 2005),
EMBASE (1996 to week 9 2005) and the Cochrane Library
(1996 to Issue 1 2005). Our search strategy included MeSH
terms such as osteoporosis, postmenopausal and strontium
ranelate in addition, complementary free text words. We
limited the search to randomized controlled trials and
supplemented it to include previously completed systematic
reviews.
• A review of reference lists of relevant articles for additional
published trials.
• A hand search of abstracts from Osteoporosis International,
Journal of Bone and Mineral Research, Calcified Tissue
International and FDA proceedings from the last two years.
• Lastly, additional information was sought from authors and
industry sponsors.
MEDLINE Search Strategy
1 *Osteoporosis/
2 osteoporos#s.tw.
3 bone loss$.tw.
4 Bone Density/
5 (bone adj2 (density or fragil$)).tw.
6 bone mass.tw.
7 bmd.tw.
8 exp Fractures, Bone/
9 fracture$.tw.
10 or/1-9
11 Postmenopause/
12 (post menopaus$ or postmenopaus$ or post-menopaus$).tw.
13 11 or 12
14 10 and 13
15 clinical trial.pt.
16 randomized controlled trial.pt.
17 tu.fs.
18 dt.fs.
19 random$.tw.
20 (double adj blind$).tw.
21 placebo$.tw.
22 or/15-21
23 22 and 14
24 Strontium/
25 strontium.tw.
26 ranelate.tw.
27 prevos.tw.
28 or/24-27
29 28 and 23
30 limit 29 to yr=“1996 - 2005”
Embase Search Strategy
1 exp osteoporosis/
2 bone loss$.tw.
3 osteoporos#s.tw.
4 bone density/
5 (bone adj2 (density or fragil$)).tw.
6 bone mass.tw.
7 bmd.tw.
8 exp Fracture/
9 fracture$.tw.
10 or/1-9
11 postmenopause/
12 (post menopaus$ or postmenopaus$ or post-menopaus$).tw.
13 11 or 12
14 10 and 13
15 random$.tw.
16 factorial$.tw.
17 crossover$.tw.
18 placebo$.tw.
19 (singl$ adj blind$).tw.
20 (doubl$ adj blind$).tw.
21 assign$.tw.
22 allocat$.tw.
23 volunteer$.tw.
24 randomized controlled trials/
25 double-blind method/
26 single-blind method/
27 or/15-26
28 27 and 14
29 STRONTIUM/
30 strontium.tw.
31 ranelate.tw.
32 prevos.tw.
33 or/29-32
34 27 and 33
35 limit 34 to yr=“1996 - 2005”
M E T H O D S O F T H E R E V I E W
Study selection, quality assessment and data extraction:
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The bibliographic record (i.e. title, authors, keywords and abstract)
retrieved from the search were assessed by two independent
reviewers (SO’D, AC) for potential eligibility based on the review’s
a priori eligibility criteria. Those records deemed potentially
eligible, or those in which there was not enough information,
underwent a full text review to confirm their inclusion.
Methodological quality was assessed by two independent reviewers
(SO’D, AC) using a validated instrument by Jadad (Jadad 1996).
This checklist includes three items pertaining to descriptions of
randomization, blinding, and the inclusion of data for dropouts
and withdrawals, with a total score of five. Studies with a score
less than or equal to two were considered low quality studies.
Allocation concealment was also evaluated by two independent
reviewers (SO’D, AC) using the allocation component of a
validated instrument (Schulz 1995). As outlined in the Cochrane
Reviewer’s Handbook, the allocation concealment was determined
to be: A) adequate i.e. central randomization; numbered or coded
bottles or containers; drugs prepared by the pharmacy; serially
numbered, opaque, sealed envelopes; or other description that
contained elements convincing of concealment, B) unclear i.e.
authors either did not report an allocation concealment approach
at all or reported an approach that was neither adequate nor
inadequate, C) inadequate i.e. alternation or reference to case
record numbers or to dates of birth, and D) not used. Next,
data were independently extracted by both reviewers (SO’D, AC)
using a data extraction form designed specifically for this review.
Details of the study population, duration of intervention, baseline
demographic data, and the outcomes were collected. Differences
with respect to article eligibility, quality assessment and data
extraction were resolved by referring to the original publication
and establishing consensus (Alderson 2003).
Grading the strength of the evidence per outcome:
We used the ribbon grading system as described in the 2004
Evidence-based Rheumatology BMJ book (Tugwell 2004) to grade
the strength of the evidence per outcome. The ribbon grading
system uses four categories to rank the evidence from research
studies: Platinum, Gold, Silver and Bronze. The ranking is given
according to different criteria, including sample size, blinding,
handling of withdrawals and concealment allocation (Tugwell
2004). The ranking of the efficacy outcomes (i.e. fractures and
BMD) is included in the synopsis, methodological quality of
included studies and the clinical relevance tables (see Additional
Tables - 01 and 02) of this review.
Data analysis:
Prior to the pooling, we developed hypotheses that might account
for heterogeneity of study results and compared groups according
to: 1) treatment duration, 2) dose and, 3) prevention versus
treatment populations. Where possible, the analyses were based
on intention-to-treat data from the individual clinical trials.
For fractures and safety outcomes, a weighted relative risk was
determined for the number of women with either incident
fractures or adverse events using Review Manager 4.2.7 (Fleiss
1993). For BMD, a weighted mean difference (WMD) of the
percent change between treatment and control groups for different
BMD sites including lumbar spine, femoral neck and total hip
was calculated. Analyses of the four trials were conducted using
an available data set as it was not possible to carry out an
intention to treat analysis with the published data. Meta-analysis
was conducted according to random effects model. Heterogeneity
of the treatment effect was calculated using a chi-square test with
n -1 degrees of freedom; where n is the number of studies and
the I2 statistic (Fleiss 1993; Higgins 2003). In addition to relative
measures, the absolute risk reduction (ARR) was calculated and
for those outcomes that were statistically significant, the number
needed to treat (NNT) was determined. The NNT was calculated
by taking the inverse of the ARR (NNT = 1/ARR) where ARR is
the control event rate minus the treatment event rate. These results
are summarized in the clinical relevance tables of this review (see
Additional Tables - 01 and 02).
D E S C R I P T I O N O F S T U D I E S
A total of 80 potentially relevant studies were identified from the
electronic and hand search strategy outlined above and screened
for retrieval. Of these, 62 were excluded as they did not meet the
review’s eligibility criteria and 18 underwent a full text review (Me-
unier 2003; Meunier 2004-3; Meunier 2002; Meunier 2004-1;
Reginster 2002-1; Reginster 2005; Boivin 2003; Meunier 2004-
2; Naveau 2004; Pors 2004; Reginster 2002-2; Reginster 2003-
1; Reginster 2003-2; Reginster 2004; Reginster 2004-1; Sorbera
2003; Uebelhart 2003; Marquis 2005). Of these 18 records, a to-
tal of 13 were excluded as a result of being either a review pub-
lication (Meunier 2004-2; Reginster 2003-1; Meunier 2004-3;
Boivin 2003; Naveau 2004; Pors 2004; Reginster 2002-2; Re-
ginster 2003-2; Reginster 2004; Reginster 2004-1; Sorbera 2003;
Uebelhart 2003) or a description of the study protocol (Meunier
2003). The remaining five studies met our eligibility criteria, four
of which were primary studies (Meunier 2002; Meunier 2004-1;
Reginster 2002-1; Reginster 2005) and one, an abstract, that was
a companion paper to the included study by Meuneir et al., 2004
(Marquis 2005). There was no previous systematic review on this
topic.
All four included primary studies were randomized placebo con-
trolled trials (Meunier 2002; Meunier 2004-1; Reginster 2002-
1; Reginster 2005). Three investigated the efficacy of strontium
ranelate in a treatment population (Meunier 2002; Meunier 2004-
1; Reginster 2005) and one included a prevention population (Re-
ginster 2002-1). The mean age of the postmenopausal women
studied ranged from 54.2 (Reginster 2002-1) to 76.7 years (Regin-
ster 2005). None of the women had a previous vertebral fracture in
one study (Reginster 2002-1), approximately half had a prior ver-
tebral fracture in one (Reginster 2005) and all of the women had
a prior vertebral fracture in two (Meunier 2002; Meunier 2004-
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1). The women’s mean BMD T score was < - 2.5 SD in three
(Meunier 2002; Meunier 2004-1; Reginster 2005) and > - 2.5 SD
in one (Reginster 2002-1). With respect to dosages of strontium
ranelate received, the three treatment studies included the recom-
mended daily dose of strontium ranelate (2g) (Meunier 2002; Me-
unier 2004-1; Reginster 2005) whereas in the prevention trial; the
highest daily dose was 1 g (Reginster 2002-1). The compliance
rate ranged from 80% (Reginster 2005) to 93% (Meunier 2002).
All four studies included a calcium supplement in both treatment
and control groups which ranged in dose from 500 mg (Meunier
2002; Reginster 2002-1) to 1000 mg (Meunier 2004-1; Reginster
2005) daily. In three trials, women in the treatment and control
groups also received vitamin D supplements which ranged from
400 to 800 IU daily based on serum concentrations of 25-hydrox-
yvitamin D (Reginster 2005; Meunier 2004-1) or 800 IU daily
(Meunier 2002). No other osteoporotic treatments were admin-
istered. Three studies assessed vertebral fractures (Meunier 2002;
Meunier 2004-1; Reginster 2005) and two included non-vertebral
fractures (Meunier 2004-2; Reginster 2005). All four studies mea-
sured BMD, three of which assessed BMD of the lumbar spine
(Meunier 2002; Reginster 2002-1; Meunier 2004-1), three at the
total hip (Reginster 2002-1; Meunier 2004-1; Reginster 2005)
and four at the femoral neck (Meunier 2002; Reginster 2002-1;
Meunier 2004-1; Reginster 2005). Quality of life was assessed in
two trials (Meunier 2004-1; Reginster 2005). Total withdrawals,
withdrawals due to adverse events, emergent adverse events, se-
rious adverse events and deaths were reported in all four stud-
ies (Meunier 2004-1; Reginster 2002-1; Reginster 2005; Meunier
2002) whereas the number of individuals that developed diarrhea
or gastritis was reported in three (Meunier 2002; Meunier 2004-
1; Reginster 2005). Additional details regarding the characteris-
tics of the included studies are presented in the Characteristics of
Included Studies Table of this review.
M E T H O D O L O G I C A L Q U A L I T Y
The quality of the included studies was assessed using the Jadad
instrument (Jadad 1996). Quality scores, percent lost to follow-up
and allocation concealment grades are summarized in the Charac-
teristics of Included Studies Table of this review. All four studies
were adequately reported as randomized and described adequate
methods regarding the sequence of randomization. All reported
that the trial was double blind and of these, two indicated that the
recipients of care were unaware of their assigned intervention (Re-
ginster 2002-1; Reginster 2005). One reported that the persons
responsible for assessing outcomes were unaware of the assigned
intervention (Meunier 2004-1) and one reported that the recipi-
ents, those providing the care and persons responsible for assessing
outcomes were all unaware of the assigned intervention (Meunier
2002). A description of withdrawals was adequately provided in
all trials. All trials had a methodological quality score of greater
than three out five on the Jadad checklist (mean 4.25, range 4-5).
Despite the high quality of the included studies, three had losses
to follow-up greater than 20% (Meunier 2002; Meunier 2004-1;
Reginster 2005) and only one provided an adequate description of
allocation concealment (Meunier 2002). Lastly, the analyses of the
four trials were conducted using an available analysis set, which is
not preferred but close to the intention to treat’ principle (Alder-
son 2003). For the efficacy outcomes of this review (fractures and
BMD), a “silver” level of evidence has been assigned as none of the
randomized trials met all of the criteria required for a gold level
ranking i.e. sample size of at least 50 in each group, blinding of
patients and assessors for outcomes, loss to follow-up < 20% and
adequate allocation concealment (Tugwell 2004).
R E S U L T S
FRACTURES:
Vertebral Fractures:
Vertebral fractures were determined by the quantitative morpho-
metric assessment method by Genant (Meunier 2002; Meunier
2004-1) and semi-quantative visual assessments (Meunier 2004-
1; Reginster 2005). Patients were not obligated to undergo a ver-
tebral x-ray in one of the phase III trials however, x-rays were ob-
tained for the largest number of patients as possible (total of 3640
patients or 71%) (Reginster 2005).
In osteoporotic women, 2 g of strontium ranelate per day demon-
strated a 41% relative reduction in radiographic vertebral fractures
over a one year period (three trials, n=5254, RR 0.59, 95% CI
0.46 to 0.74) (Meunier 2002; Meunier 2004-1; Reginster 2005)
and a 37% relative reduction over a three year period (two trials,
n = 5082, RR 0.63, 95% CI 0.56 to 0.71) compared to placebo
(Meunier 2004-1; Reginster 2005). The chi-square test for het-
erogeneity of treatment effect was not significant in either of these
analyses (i.e. p > 0.1).
There was only one trial (n=1442) that investigated the effects of
2 g of strontium ranelate versus placebo per day on symptomatic
or clinical vertebral fractures in osteoporotic women (Meunier
2004-1). The results from this trial demonstrated a 52% relative
reduction in risk of a symptomatic fracture (RR 0.48, 95% CI
0.29 to 0.80) over a one year period and a 38% relative reduction
(RR 0.62, 95% CI 0.47 to 0.83) over three years.
With respect to the lower doses of strontium ranelate, one trial
demonstrated a 31% relative reduction in radiographic vertebral
fractures in osteoporotic women using 0.5 g of strontium ranelate
versus placebo per day over a two year period however, this was
not statistically significant (RR 0.69, 95% CI 0.47 to 1.01) (Me-
unier 2004-1). The same study showed a 6% relative reduction in
radiographic vertebral fractures using 1.0 g of strontium ranelate
daily over the same time frame again, this was not statistically sig-
nificant (RR 0.94, 95% CI 0.68 to 1.30) (Meunier 2004-1).
Non-vertebral Fractures:
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Non-vertebral fractures were reported by study investigators based
on radiographic evaluation or written documentation provided
e.g. radiological report, copy of the hospitalization/emergency de-
partment report (Meunier 2004-1, Reginster 2005).
In osteoporotic women, 2 g of strontium ranelate per day demon-
strated a 14% relative reduction in all non-vertebral fractures (in-
cluding hip but excluding fractures of the coccyx, skull, jaw, face,
ankle, fingers and toes) over a three year period compared to
placebo (two trials, n = 6572, RR 0.86, 95% CI 0.75 to 0.98)
(Meunier 2004-1; Reginster 2005). However, the upper boundary
of the confidence interval approximates one. The chi-square test
for heterogeneity of treatment effect was not significant.
One study (n = 4932) reported on major osteoporotic non-verte-
bral fractures defined as fractures of the wrist, pelvis and sacrum,
ribs-sternum, clavicle, humerus or hip only in women with osteo-
porosis and found a 19% relative reduction taking 2 g strontium
ranelate daily compared to placebo although the upper boundary
of the confidence interval approaches one (RR 0.81, 95% CI 0.66
to 0.98) (Reginster 2005).
There were no studies that evaluated the effects of lower doses of
strontium ranelate on the incidence of non-vertebral fractures.
Hip:
There was only one trial that assessed the efficacy of 2 g of stron-
tium ranelate per day versus placebo on the relative reduction of
hip fractures in women with osteoporosis (Reginster 2005) there-
fore, we were unable to estimate a pooled relative risk. Hip frac-
tures, similar to other non-vertebral fractures, were determined
by a radiological evaluation or by a report from a hospitalization.
After three years, the relative risk of a hip fracture was 15% (RR
0.85, 95% CI 0.61 to 1.19) in the total group of women (n=4932)
versus 36% for a subgroup at high risk of hip fracture (n=1977)
defined by age > 74 years and a femoral neck BMD T-score < - 3
(Looker 1991) (RR 0.64, 95% CI 0.41 to 0.99). In both instances
the treatment effect was not statistically significant. However, this
study was not powered for this efficacy outcome.
BMD:
Lumbar Spine BMD:
Using 2 g of strontium ranelate daily versus placebo, an increase
in lumbar spine BMD was demonstrated in osteoporotic women
over a two year period (two trials, n = 1614, WMD adjusted for
strontium content 5.44, 95% CI 3.41 to 7.46 and WMD, not
adjusted for strontium content 11.29, 95% CI 10.22 to 12.37)
(Meunier 2002; Meunier 2004-1). However, the chi-square test
for heterogeneity of treatment effect was significant for the anal-
ysis involving the results adjusted for strontium content (p=0.04)
and I2 = 76.6%. We investigated sources of clinical heterogeneity
and a possible explanation relates to the difference in timing and
methods of the strontium content calculation from bone-biopsy
samples between the two trials (Meunier 2004-1; Meunier 2002).
There was only one trial (n=1442) that investigated the effects
of 2 g of strontium ranelate daily versus placebo in osteoporotic
women on lumbar spine BMD over a three year period and the
WMD demonstrated an increase in lumbar spine BMD relative
to placebo (WMD adjusted for strontium content 8.09, 95% CI
7.22 to 8.96 and WMD not adjusted for strontium content 14.39,
95% CI 13.40 to 15.38) (Meunier 2004-1).
In terms of the lower doses of strontium ranelate, one study (n=63)
investigated the effects of 0.125 g of strontium ranelate daily ver-
sus placebo on women without osteoporosis and found a non-
significant increase in lumbar spine BMD over a two year period
(WMD not adjusted for strontium content 0.37, 95% CI -1.57 to
2.31) (Reginster 2002-1). Women, with and without osteoporo-
sis, taking 0.5 g of strontium ranelate daily compared to placebo
showed a non-significant increase in lumbar spine BMD over a
two year period when BMD was adjusted for strontium content
(two trials, n = 232, WMD 1.01, 95% CI -0.63 to 2.66). However,
when BMD was not adjusted for strontium content, the increase
was significant (WMD 3.59, 95% CI 1.66 to 5.51) (Meunier
2002; Reginster 2002-1). The chi square test for heterogeneity
of treatment effect for the analyses where BMD was not adjusted
for strontium content was approaching significance (p=0.16) and
I2 = 49.5%. The inclusion of a treatment (Meunier 2002) versus
prevention (Reginster 2002-1) population may explain this find-
ing. Lastly, women with and without osteoporosis, taking 1 g of
strontium ranelate daily compared to placebo demonstrated an
increase in lumbar spine BMD over a two year period (Meunier
2002; Reginster 2002-1) (two trials, n = 232, WMD adjusted for
strontium content 2.14, 95% CI 0.70 to 3.58 and WMD, not
adjusted for strontium content 6.68, 5.16 to 8.20). The chi square
test for heterogeneity of treatment effect was not significant.
Femoral Neck BMD:
The effects of taking 2 g of strontium ranelate daily versus placebo
in osteoporotic women demonstrated an increase in femoral neck
BMD over two year (two trials, n=1614, WMD 5.73, 95% CI
5.15 to 6.32) (Meunier 2002; Meunier 2004-1) and three year
period (two trials, n=4230, WMD 8.25%, 95% CI 7.84 to 8.66)
(Meunier 2004-1; Reginster 2005). The chi-square test for het-
erogeneity of the treatment effect was not significant for both of
these analyses.
With respect to the lower doses of strontium ranelate, one trial
(n = 63) explored the effects of 0.125 g/day in women without
osteoporosis and found a non significant increase in femoral neck
BMD in favour of those receiving the placebo over a two year
period (WMD -1.47, 95% CI -3.68 to 0.74) (Reginster 2002-
1). The effects of 0.5 g of strontium ranelate daily versus placebo
demonstrated a non-significant increase in femoral neck BMD
(two trials, n = 232, WMD 1.00, 95% CI -0.52 to 2.52) whereas
1 g of strontium ranelate daily versus placebo showed a significant
increase (two trials, n = 233, WMD 2.52, 95% CI 0.96 to 4.09)
over a two year period (Meunier 2002; Reginster 2002-1). The chi
8Strontium ranelate for preventing and treating postmenopausal osteoporosis (Review)
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square test for heterogeneity of treatment effect was not significant
for either of these analyses.
Total Hip BMD:
One study (n=1442) demonstrated an increase in total hip BMD in
osteoporotic women on 2 g of strontium ranelate daily compared
to placebo over a two year period (WMD 1.16, 95% CI 1.05-
1.27) (Meunier 2004-1) and two trials (n=4230) demonstrated an
increase in total hip BMD over a three year period (WMD 9.83,
95% CI 9.39 to 10.26). The chi-square test for heterogeneity of
treatment effect for the latter analyses was not significant.
Only one trial investigated the effects of lower doses of strontium
ranelate on total hip BMD and found a non-significant increase
with 0.125 g of strontium ranelate daily (n= 63, WMD 0.67, 95%
CI -1.18 to 2.52) and significant increases with 0.5 g/day (n=65,
WMD 2.02, 95% CI 0.47 to 3.57) and 1 g/day (n=60, WMD
4.09, 95% CI 2.09 to 6.09) over a two year period (Reginster
2002-1).
Health Related Quality of Life:
Quality of life was assessed using the SF-36 questionnaire in two
trials (Meunier 2004-1; Reginster 2005) as well as the Quality of
Life questionnaire in Osteoporosis (QUALIOST) in one (Meu-
nier 2004-1). The QUALIOST is a 23 item, disease specific (verte-
bral osteoporosis) questionnaire, with a global score and two sub-
scores: physical and emotional. In both trials, women completed
the quality of life assessments at baseline and every six months
throughout the duration of the trial (Meunier 2003). The results
are not within the published literature however, unpublished data
demonstrated that 2 g of strontium ranelate daily compared to
placebo has a beneficial effect on quality of life as defined by the
QUALIOST in a subset of osteoporotic women (n=1240) after
three years of treatment (global score p = 0.016, emotional and
physical scores p = 0.019 and 0.032 respectively) (Marquis 2005).
Furthermore, results from a back pain assessment included in the
QUALIOST questionnaire conducted every six months, revealed
that the occurrence of back pain was significantly reduced by 29%
in the strontium ranelate group as compared to the placebo group
over three years with a significant effect in the first year (p = 0.006)
(Marquis 2005).
ADVERSE EVENTS:
All adverse event data was reported by dose regardless of study
duration i.e. two years (Meunier 2002; Reginster 2002-1) and
three years (Meunier 2004-1; Reginster 2005).
Total withdrawals:
A total of three trials (n = 6847) using the recommended dose of
2 g strontium ranelate versus placebo daily did not find a signifi-
cant difference in the risk of withdrawals (RR 0.98, 95% CI 0.91
to 1.05) (Meunier 2002; Meunier 2004-1; Reginster 2005). The
chi-square test for heterogeneity of the treatment effect was not
significant. Similarly, two trials (n=256) using 0.5 g of strontium
ranelate versus placebo daily did not demonstrate a significant dif-
ference in the risk of withdrawal (RR 0.87, 95% CI 0.36 to 2.11)
(Meunier 2002; Reginster 2002-1). The chi square test was ap-
proaching significance (p=0.11) and I2 = 60.7% which may be
explained by the inclusion of a treatment (Meunier 2002) versus
prevention (Reginster 2002-1) population.
Withdrawals due to adverse events:
A total of three trials (n = 6847) reported the safety of using the
recommended daily dose of 2 g strontium ranelate versus placebo
through withdrawals due to adverse events (Meunier 2002; Meu-
nier 2004-1; Reginster 2005). The pooled estimate of the relative
risk was 1.20 (95% CI 0.96 to 1.50) with 22% of the strontium
ranelate treated patients versus 19.1% of the controls having with-
drawn due to an adverse event however, this finding was not signif-
icant (p=0.12). The chi-square test for heterogeneity of the treat-
ment effect was borderline significant (p=0.10) and I2=57.0%.
This may be attributed to differences in the study populations
baseline characteristics including age and frailty (i.e. fracture preva-
lence). Similarly, for those women taking 0.5 g/day, there was no
significant difference in the risk of withdrawals due to adverse
events (two trials, n=256, RR 1.10, 95% CI 0.56 to 1.80) (Meu-
nier 2002; Reginster 2002-1). The chi square test for heterogene-
ity was not significant.
Number of emergent adverse events:
A total of three trials (n = 6847) using the recommended daily
dose of 2 g of strontium ranelate versus placebo daily did not find
a significant difference in the number of emergent adverse events
(RR 0.99, 95% CI 0.98 to 1.01). (Meunier 2004-1; Meunier
2004-1; Reginster 2005). Similarly, two trials (n=256) using 0.5 g
of strontium ranelate versus placebo daily did not find a significant
difference in the risk of developing an adverse event (RR 0.93,
95% CI 0.86 to 1.00) (Meunier 2002; Reginster 2002-1). The
chi-square test for heterogeneity of the treatment effect was not
significant for either of these analyses.
Serious adverse events:
A total of three trials (n = 6847) reported the number of partic-
ipants that developed a serious adverse event using 2 g of stron-
tium ranelate daily versus placebo (Meunier 2002; Meunier 2004-
1; Reginster 2005). Serious adverse events occurred in 24.09% of
the strontium ranelate treated patients versus 23.97% of the con-
trols. The pooled estimate of the relative risk was 1.01 (95% CI
0.92 to 1.09) demonstrating a non significant difference between
the two groups. Similarly, two trials (n=256) reported the number
of serious adverse events using 0.5 g of strontium ranelate versus
placebo daily and found no significant difference in the relative
risk of developing a serious adverse event (RR 0.81, 95% CI 0.44
to 1.48) (Meunier 2002; Reginster 2002-1). The chi-square test
for heterogeneity of the treatment effect was not significant for
either of these analyses.
Diarrhea:
A total of three trials (n = 6847) reported the number of partic-
ipants that developed diarrhea using the recommended dose of
9Strontium ranelate for preventing and treating postmenopausal osteoporosis (Review)
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strontium ranelate versus placebo daily (Meunier 2004-1; Meu-
nier 2002; Reginster 2005). Diarrhea occurred in 6.5% of the
strontium ranelate treated patients versus 4.7% in the controls.
The pooled estimate of the relative risk was 1.38 (95% CI 1.02 to
1.87) with an overall significant effect (p = 0.04). The chi-square
test for heterogeneity of the treatment effect was not significant.
Gastritis:
A total of three trials (n = 6847) reported the number of partici-
pants that developed gastritis using 2 g of strontium ranelate versus
placebo daily (Meunier 2002; Meunier 2004-1; Reginster 2005).
Gastritis occurred in 2.7% of the strontium ranelate treated pa-
tients and 3.4% of the controls. The pooled estimate of the rela-
tive risk was 0.81 (95% CI 0.56 to 1.17). The chi-square test for
heterogeneity of the treatment effect was not significant.
Deaths:
A total of three trials (n = 6847) reported the total number of deaths
using 2 g of strontium ranelate versus placebo daily (Meunier
2002; Meunier 2004-1; Reginster 2005). A total of 4.97% of the
strontium ranelate treated patients versus 5.37% of the controls
died during the follow-up period. The pooled estimate of the
relative risk was 0.99 (95% CI 0.64 to 1.53). The chi-square test
for heterogeneity of the treatment effect was borderline significant
with p= 0.17 and I2= 42.8%. This may be attributed to differences
in the mean age of the study population in addition to their frailty.
Additional data obtained suggests that the risk of vascular sys-
tem disorders including venous thromboembolism (two trials, n
= 6669, 2.2% versus 1.5%, OR 1.5, 95% CI 1.1 to 2.1) and pul-
monary embolism (two trials, n = 6669, 0.8% versus 0.4%, OR
1.7, 95% CI 1.0 to 3.1) as well as nervous system disorders such
as headaches (3.9% versus 2.9%), seizures (0.3% versus 0.1%),
memory loss (2.4% versus 1.9%) and disturbance in conscious-
ness (2.5% versus 2.0%) is slightly increased with taking 2 g of
strontium ranelate daily over a 3 to 4 year period.
D I S C U S S I O N
A total of four trials met our inclusion criteria, three of which
investigated the effects of strontium ranelate compared to placebo
in a treatment population (doses ranged from 0.5 to 2 g daily) and
one, in a prevention population (doses 0.125, 0.5 and 1 g daily).
The included studies were presumably conducted in calcium and
vitamin D replete postmenopausal women.
There is silver level evidence to support the use of 2 g of strontium
ranelate daily in osteoporotic postmenopausal women to reduce
the risk of vertebral and to a lesser extent, non-vertebral fractures.
The pooled estimate of the relative risk for vertebral and non-ver-
tebral fractures over a three year follow-up period were consistent
with a reduction of 37% for vertebral fractures and 14% for non-
vertebral fractures. Both estimates were statistically significant and
there was little heterogeneity of treatment effect however, the up-
per boundary of the confidence interval of the non-vertebral frac-
tures approaches one indicating that the data may be consistent
with a null effect. Furthermore, the impact that 2 g of strontium
ranelate daily has on reducing the risk of a hip fracture remains un-
clear as the only included study with data was not powered for this
outcome. Although data from direct comparisons with other anti-
osteoporotic treatments are lacking, the reduction in the relative
risk of vertebral fracture seems similar to the other available thera-
pies which have been shown to reduce the relative risk of recurrent
fracture by 40 to 60% (Cranney 2002). The greater reduction in
risk of vertebral fractures compared to non-vertebral fractures may
be explained by the greater effect that strontium ranelate has on
the vertebral versus non-vertebral bone mineral density.
The results of this review support the use of 2 g of strontium
ranelate daily in osteoporotic postmenopausal women for increas-
ing BMD at all sites over a two to three year period. In a preven-
tion population, 1 g of strontium ranelate daily was demonstrated
to increase BMD at all sites compared to placebo over a two year
period. In both the treatment and prevention populations, lower
doses of strontium ranelate were superior to placebo with the high-
est dose of strontium ranelate demonstrating the greatest increase
in BMD over a two year period. While the increase in BMD in
patients taking 2 g of strontium ranelate daily is impressive, cau-
tion is necessary when in interpreting these results. As previously
mentioned, the combined effect of strontium distribution in bone
and increased x-ray absorption of strontium compared to calcium
leads to an amplification of BMD measurement by DXA (Or-
tolani 2006). While the included trials described and performed
a correction to adjust for the strontium content in bone for the
lumbar spine BMD measurements, there is considerable uncer-
tainty about the accuracy of the results which arises from the small
number of participants in whom iliac crest bone biopsy was per-
formed and the reliance on animal data for the correction factor
for inferring bone strontium content in the spine (Blake 2005).
Although limited, there is evidence from one phase III trial to
suggest that 2 g of strontium ranelate daily compared to placebo
has a beneficial effect on health related quality of life in a subset of
postmenopausal women (n=1240) after three years of treatment.
In keeping with this, results from a back pain assessment included
in the quality of life questionnaire revealed that the occurrence
of back pain was significantly reduced by 29% in the strontium
ranelate group as compared to the placebo group over three years
with a significant effect in the first year (p = 0.006) (Marquis
2005). These findings are presumably due to a reduction in the
consequences related to osteoporosis such as vertebral fractures.
Overall incidence rates for adverse events with strontium ranelate
did not differ from placebo regardless of dose. There was a statisti-
cally significant increase in the risk for diarrhea in patients treated
with 2 g of strontium ranelate daily relative to placebo. However;
there was no significant difference in the number of withdrawals
10Strontium ranelate for preventing and treating postmenopausal osteoporosis (Review)
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INTERNAL U
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due to side effects, number of emergent events, serious adverse
events, gastritis or deaths regardless of the dose analyzed. Addi-
tional data obtained from the scientific report by the European
Agency for the Evaluation of Medicinal Products (EMEA 2004),
in addition to the industry sponsor (Servier), has illustrated some
concern of a slight increased risk in vascular and neurological dis-
orders as well as abnormal laboratory findings. This information
is based on results from the two phase III trials which focused on
the recommended dose of 2 g of strontium ranelate daily (Meu-
nier 2004-1; Reginster 2005) and has been summarized below and
within the appended table entitled “Other adverse events from
additional sources” (see Additional Tables -02).
Disorders of the vascular system were present in 26.3% of the pa-
tients in the strontium ranelate group versus 24.4% in the placebo;
Estimated difference = 1.9% (95% CI -0.2 to 4.0) with an in-
creased reporting rate of adverse events of venous thromboem-
bolism (2.2% versus 1.5%, OR 1.5, 95% CI 1.1 to 2.1) and pul-
monary embolism (0.8% versus 4.5%, OR 1.7, 95% CI 1.0 to
3.1) over a three year period. Furthermore, the absolute number
of patients that suffered a pulmonary embolism resulting in dis-
continuation of treatment or death was slightly increased in the
strontium ranelate group compared to controls (i.e. 0.2% versus
0.1%). The cause of this increased risk of vascular disorders is not
understood. Nervous system disorders were found in 20.9% of
the patients in the strontium ranelate group versus 18.9% in the
placebo; Estimated difference = 2.0 % (95% CI 0.1 to 3.9) with
an increased reporting of seizures (0.3% versus 0.1%), memory
loss (2.4% versus 1.9%) and disturbances in consciousness (2.5%
versus 2.0%) over a four year period. Again, the etiology of the
increased risk in neurological disorders is not clear. Lastly, mean
baseline serum creatine kinase levels increased in both groups how-
ever, this increase was significantly greater in the strontium ranelate
group (31.3 + 80.8 IU/L) compared to the controls (13.1 + 46.6
IU/L); Estimated difference = 18.2 IU/L (95% CI 14.8 to 21.6).
The serum creatine kinase levels was greater than the upper limit
of normal on at least one occasion in 29.4% (789/2680) of the
women in the strontium ranelate group versus 17.6% (475/2705)
of the controls (RR 1.68, 95% CI 1.52 to 1.85) providing evidence
of strontium ranelate impacting skeletal muscle cell integrity. In
light of these findings targetted surveillance will be needed (EMEA
2004).
Our systematic review has several limitations. Firstly, while the
methodological quality of the included studies was high based on
the Jadad instrument, three of the four studies had losses to follow-
up greater than 20% (Meunier 2002; Meunier 2004-1; Reginster
2005) and three had unclear descriptions of allocation conceal-
ment (Meunier 2004-1; Meunier 2004-1; Reginster 2005). Losses
to follow-up can threaten the validity of the trial since the event
rate may be very different in those lost to follow-up versus those
who completed the trial and failure to conceal the participants’
treatment allocation could also bias the treatment effect in either
direction. Secondly, access to aggregate data only within the pub-
lished studies resulting in pooling of proportions and limiting our
ability to adjust for differences in patient populations.
This review will be updated every two years (or earlier) depending
on the emergence of new evidence. Review updates will entail re-
peating, at periodic intervals, the steps involved in the original re-
view. If new evidence addresses important variables that were not
included in the original review we will consider including them.
In such instances, we will recheck whether any of their earlier
identified studies had such information that was overlooked. Fur-
thermore, should we decide to include a new analysis strategy in
our updated review we understand that any new analysis strategies
represents a substantive change to the review requiring editorial
critique through the Cochrane Collaboration’s established edito-
rial process.
A U T H O R S ’ C O N C L U S I O N S
Implications for practice
There is silver level evidence to support the usefulness of strontium
ranelate in reducing fractures in postmenopausal osteoporotic
women and increasing BMD in women with/without osteoporo-
sis. Pooled estimates using 2 g of strontium ranelate daily com-
pared to placebo in osteoporotic women over a three year period
are consistent with a reduction in vertebral fractures (37%); how-
ever, there is less of a reduction in non-vertebral fractures (14%)
and the effect on hip fractures remains unclear. Strontium ranelate
increased BMD at all sites in both treatment and prevention pop-
ulations and while lower doses of strontium ranelate were superior
to placebo, the highest dose demonstrated the greatest increase.
There is some evidence to suggest that 2 g of strontium ranelate
daily compared to placebo may have a beneficial effect on health
related quality of life in postmenopausal women after three years
of treatment. Diarrhea may occur however, adverse events leading
to study withdrawal were not significantly increased in the stron-
tium ranelate group. Potential risks to the vascular and neurolog-
ical system associated with taking 2 g of strontium ranelate daily
need to be further explored and quantified.
Implications for research
Further monitoring of the quality, effectiveness and safety of stron-
tium ranelate is essential especially in the prevention of osteo-
porosis. Additional research is required to confirm its mechanism
of action. Long term fracture data are needed to confirm the ef-
fect that strontium ranelate has on bone health in both preven-
tion and treatment populations. Long term safety data is required
with particular attention to be paid to bone mineralization, con-
tinued fracture efficacy, neurological and vascular system disor-
ders, specifically venous and pulmonary thromboembolism and
skeletal muscle integrity. Future trials to evaluate the impact of
strontium ranelate treatment on BMD, including the effect on
the elimination of bone strontium in patients switching to other
11Strontium ranelate for preventing and treating postmenopausal osteoporosis (Review)
Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
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anti-resorptive treatments, are needed. In addition, comparative
trials evaluating the efficacy of strontium ranelate relative to other
osteoporosis therapies such as bisphosphonates and intermittent
recombinant human parathyroid hormone are required.
P O T E N T I A L C O N F L I C T O F
I N T E R E S T
None known.
A C K N O W L E D G E M E N T S
The authors would like to thank Louise Falzon of the Cochrane
Musculoskeletal Group for her assistance in developing the search
strategy and Patricia Chatelain from Servier who provided addi-
tional data not found within the published literature.
S O U R C E S O F S U P P O R T
External sources of support
• Canadian Institutes for Health Research CANADA
Internal sources of support
• Ottawa Health Research Institute CANADA
R E F E R E N C E S
References to studies included in this review
Meunier 2002 {published data only}
Meunier PJ, Slosman DO, Delmas PD, Sebert JL, Brandi ML, Al-
banese C, Lorenc R, Pors-Nielsen S, de Vernejoul MC, Roces A, Re-
ginster JY. Strontium ranelate: Dose-dependent effects in established
postmenopausal vertebral osteoporosis - a 2-year randomized placebo
controlled trial. Journal of clinical endocrinology and metabolism 2002;
87(5):2060–2066.
Meunier 2004-1 {published data only}
Meunier PJ, Roux C, Seeman E, Ortolani S, Badurski JE, Spector
TD, Cannata J, Balogh A, Lemmel E, Pors-Nielson S, Rizzoli R,
Genant HK, Reginster J. The effects of strontium ranelate on the risk
of vertebral fracture in women with postmenopausal osteoporosis.
New england journal of medicine 2004;350(5):459–468.
Reginster 2002-1 {published data only}
Reginster JY, Deroisy R, Dougados M, Jupsin I, Colette J, Roux C.
Prevention of early postmenopausal bone loss by strontium ranelate:
The randomized, two-year, double-masked, dose-ranging, placebo-
controlled PREVOS study. Osteoporosis international 2002;13:925–
931.
Reginster 2005 {published data only}
Reginster JY, Seeman E, de Vernejoul MC, Adami S, Compston J,
Phenekos C, Devogelaer JP, Diaz Curiel M, Sawicki A, Goemaere S,
Sorensen OH, Felsenberg D, Meunier PJ. Strontium ranelate reduces
the risk of nonvertebral fractures in postmenopausal women with
osteoporosis: TROPOS study. Journal of clinical endocrinology and
metabolism 2005;90(5):2816–2822.
References to studies excluded from this reviewBoivin 2003
Boivin G. Bone mineralization and mineral status. Therapie 2003;
58(5):409–413.
Meunier 2003
Meunier PJ, Reginster JY. Design and methodology of the phase
3 trials for the clinical development of strontium ranelate in the
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Meunier 2004-2
Meunier PJ, Roux C, Seeman E, Pagalilauan G, Laya M. Strontium
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Meunier 2004-3
Meunier PJ, Roux C, Seeman E, Cheung A. Strontium ranelate re-
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12Strontium ranelate for preventing and treating postmenopausal osteoporosis (Review)
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teoporosis. Evidence-based medicine 2004;9(5):149.
Naveau 2004
Naveau B. Strontium: a new treatment for osteoporosis. Joint bone
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Pors 2004
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Reginster 2002-2
Reginster JY. Strontium ranelate in osteoporosis. Current pharmaceu-
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Reginster JY, Meunier PJ. Strontium ranelate phase 2 dose-ranging
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Reginster 2003-2
Reginster JY, Deroisy R, Jupsin I. Strontium ranelate: a new paradigm
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Reginster 2004
Reginster JY, Devogelaer JP. Treatment of postmenopausal osteo-
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Reginster 2004-1
Reginster JY, Lecart MP, Deroisy R, Lousberg C. Strontium ranelate:
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Sorbera 2003
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14Strontium ranelate for preventing and treating postmenopausal osteoporosis (Review)
Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
INTERNAL U
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T A B L E S
Characteristics of included studies
Study Meunier 2002
Methods Randomized placebo controlled trial
Duration = 2 years
N = 353
Participants Postmenopausal women
(mean age 66.2, mean (SD) Lumbar spine (LS) T-score by group: -3.80 (0.94) to -.3.97 (0.95), previous
vertebral fracture 100%)
Treatment
Primary outcome: LS bone mineral density (BMD)
Interventions Strontium ranelate 0.5 g OR 1 g OR 2 g VERSUS placebo daily
(calcium supplement 500 mg daily and vitamin D 800 IU daily)
Outcomes BMD: Lumbar spine and femoral neck
Fractures: vertebral (deformities)
Notes Lost to follow-up: 81/353 (22.9%)
Quality Score: 5/5
Allocation concealment A – Adequate
Study Meunier 2004-1
Methods Randomized placebo controlled trial
Duration = 3 years
N = 1649
Participants Postmenopausal women
(mean age 69.3, mean (SD) LS T-score by group: -3.5 (1.3) to -3.6 (1.2), previous vertebral fracture 100%)
Treatment
Primary outcome: Vertebral fractures
Interventions Strontium ranelate 2g VERSUS placebo daily
(calcium supplement up to 1000 mg daily based upon dietary intake and vitamin D 400-800 IU daily based
on serum concentration of 25-hydroxyvitamin D)
Outcomes BMD: Lumbar spine, femoral neck and total hip
Fracture: Vertebral and non-vertebral
Notes Lost to follow-up: 389/1649 (23.6%)
Quality score: 4/5
Allocation concealment B – Unclear
Study Reginster 2002-1
Methods Randomized placebo controlled trial
Duration = 2 years
N = 160
Participants Postmenopausal women
(mean age 54.2, mean LS T-score by group: -1.3 to -1.5, previous vertebral fracture 0%)
Prevention
Primary outcome: LS BMD
15Strontium ranelate for preventing and treating postmenopausal osteoporosis (Review)
Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
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Interventions Strontium ranelate 125 mg OR 500 mg OR 1 g VERSUS placebo daily
(calcium supplement 500 mg daily as calcium carbonate)
Outcomes BMD: Lumbar spine, femoral neck and total hip
Notes Lost to follow-up: 17/160 (10.6%)
Quality score: 4/5
Allocation concealment B – Unclear
Study Reginster 2005
Methods Randomized placebo controlled trial
Duration = 5 years (main statistical analysis over 3 years)
N = 5091
Participants Postmenopausal women
(mean age 76.7, mean (SD) LS T-score -2.83 (1.63) to -3.24 (1.53), previous vertebral and non-vertebral
fracture 55.4 VERSUS 54.2%)
Treatment
Primary outcome: Non-vertebral fractures
Interventions Strontium ranelate 2 g VERSUS placebo daily
(calcium supplement up to 1000 mg daily based upon dietary intake and vitamin D 400-800 IU daily based
on serum concentration of 25-hydroxyvitamin D)
Outcomes BMD: Femoral neck and total hip
Fracture: Vertebral, non-vertebral, major non-vertebral (hip, wrist, pelvis and sacrum, ribs and sternum,
clavicle, humerus) and hip
Notes Lost to follow-up:
1771/5091 (34.8%)
Quality Score: 4/5
Allocation concealment B – Unclear
Characteristics of excluded studies
Study Reason for exclusion
Boivin 2003 Review publication
Meunier 2003 Review of study design
Meunier 2004-2 Review publication
Meunier 2004-3 Review publication
Naveau 2004 Review publication
Pors 2004 Review publication
Reginster 2002-2 Review publication
Reginster 2003-1 Review publication
Reginster 2003-2 Review publication
Reginster 2004 Review publication
Reginster 2004-1 Review publication
Sorbera 2003 Review publication
Uebelhart 2003 Review publication
16Strontium ranelate for preventing and treating postmenopausal osteoporosis (Review)
Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
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Characteristics of excluded studies (Continued )
A D D I T I O N A L T A B L E S
Table 01. Clinical relevance table strontium ranelate 2 g per day: Fractures & safety data
Outcome
ER in Sr
grp (%)
ER in Ctrl
grp (%)
RR (95%
CI)
ARD
(95% CI)
NNT/NNH
(95% CI)
Sr grp: #
of women
Ctrl grp:
# of
women
Rel %
Improve-
ment
Quality of
evidence
Vertebral
fracture (1
year)
117/2621
(4.5%)
206/2633
(7.8%)
0.59
(0.46,
0.74)
-4% (-7 , -
1)
25 (14, 1) 4/100 7/100 41% Silver
Vertebral
fracture (3
years)
341/2536
(13.4%)
543/2546
(21.3%)
0.63
(0.56,
0.71)
-9% (-13,
-4)
11 (8, 25) 13/100 21/100 37% Silver
Non-
vertebral
fracture (3
years)
345/3305
(10.4%)
398/3267
(12.5%)
0.86
(0.75,
0.98)
-2% (-3,
0)
50 (33, 0) 11/100 13/100 14% Silver
With-
drawals
due to
adverse
events
762/3439
(22.1%)
650/3408
(19.1%)
1.20
(0.96,
1.50)
3% (1, 6) - - - - Silver
Serious
adverse
events
828/3437
(24.1%)
816/3404
(24.0%)
1.01
(0.92,
1.09)
0% (-2, 2) - - - - Silver
Emergent
adverse
events
3028/3439
(88.0%)
3019/3408
(88.6%)
0.99
(0.98,
1.01)
-1% (-2,
1)
- - - - Silver
Gastritis 93/3439
(2.7%)
115/3408
(3.4%)
0.81
(0.56,
1.17)
-1% (-2,
1)
- - - - Silver
Diarrhea 222/3439
(6.5%)
160/3408
(4.7%)
1.38
(1.02,
1.87)
2% (0, 3) 50 (0, 33) 6/100 4/100 -38% Silver
Legend: ER =
Event rate
Ctrl =
Controls
RR =
Relative
risk
ARD =
Absolute
risk
difference
NNT =
Number
needed to
treat
# =
Number
Rel =
Relative
Sr =
Strontium
ranelate
CI = Con-
fidence
interval
NNH =
Number
needed to
harm
17Strontium ranelate for preventing and treating postmenopausal osteoporosis (Review)
Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
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Table 02. Clinical relevance table strontium ranelate 2 g per day: BMD data
Outcome (scale)
# in Sr: Ctrl
group Mean (SD) Ctrl WMD (95% CI) Abs change Rel change
Quality of
Evidence
Lumbar spine
BMD - not
adjusted (2 years)
804:810 -1.02 (6.10)* 11.29 (10.22,
12.37)
11.29 -11.1% Silver
Lumbar spine
BMD - adjusted
(2 years)
804:810 -1.18 (6.26)* 5.44 (3.41, 7.46) 5.44 -4.6% Silver
Femoral neck
BMD (2 years)
804:810 -2.18 (5.06)* 5.73 (5.15, 6.32) 5.73 -2.6% Silver
Femoral neck
BMD (3 years)
2112:2118 -2.57 (5.80)** 8.25 (7.84, 8.66) 8.25 -3.2% Silver
Total hip BMD
(3 years)
2112:2118 -2.74 (5.80)** 9.83 (9.39,
10.26)
9.83 -3.6% Silver
most
representative
study:
# = Number SD = Standard
deviation
WMD =
Weighted mean
difference
Abs = Absolute Rel = Relative
Meunier, 2004-
1*; Reginster,
2005**
Sr = Strontium
ranelate
Ctrl = Controls
Table 03. Other adverse events from additional sources (EMEA 2004* and Servier**)
Adverse event (AE) Sr (n = 3352) Control (n= 3317) ED (95% CI) OR (95% CI)
VASCULAR SYSTEM
DISORDERS
880 (26.3%)* 809 (24.4%)* 1.9% (-0.2, 4.0)* -
Thrombosis 111 (3.3%)* 72 (2.2%)* 1.1% (0.4, 1.9)* -
Venous thromboembolism at 3
years
75 (2.2%)** 50 (1.5%)** - 1.5 (1.1, 2.1)*
Venous thromboembolism at 4
years
87 (2.6%)** 61 (1.8%)** - -
Pulmonary embolism (PE) 25 (0.8%)** 15 (0.4%)** - 1.7 (1.0, 3.1)*
Fatal PE 6 (0.2%)* 3 (0.1%)* - -
PE leading to treatment
discontinuation
7 (0.2%)* 3 (0.1%)* - -
NERVOUS SYSTEM
DISORDERS
699 (20.9%)* 627 (18.9%)* 2.0% (0.1, 3.0)* -
Headaches 131 (3.9%)* 97 (2.9%)* 1.0% (0.1, 1.9)* -
Seizures at 4 years 9 (0.3%)** 3 (0.1%)** - -
Memory loss at 4 years 79 (2.4%)** 63 (1.9%)** - -
Disturbance in consciousness 83 (2.5%)** 66 (2.0%)** - -
18Strontium ranelate for preventing and treating postmenopausal osteoporosis (Review)
Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
INTERNAL U
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Table 03. Other adverse events from additional sources (EMEA 2004* and Servier**) (Continued )
Adverse event (AE) Sr (n = 3352) Control (n= 3317) ED (95% CI) OR (95% CI)
at 4 years
LABORATORY RESULTS
Serum creatine kinase 31.3 (80.8) IU/L* 13.1 (46.6) IU/L* 18.2 (14.8; 21.6) IU/L* -
Data obtained from the
EMEA* and Servier**
Sr = Strontium ranelate ED= Estimated difference OR = Odds ratio
CI = Confidence interval
A N A L Y S E S
Comparison 01. Fractures
Outcome titleNo. of
studies
No. of
participants Statistical method Effect size
01 Verterbral fractures Relative Risk (Random) 95% CI Subtotals only
02 Non-vertebral fractures Relative Risk (Random) 95% CI Subtotals only
Comparison 02. BMD
Outcome titleNo. of
studies
No. of
participants Statistical method Effect size
01 Lumbar spine BMD not
adjusted for strontium content
Weighted Mean Difference (Random) 95% CI Subtotals only
02 Lumbar spine adjusted for
strontium content
Weighted Mean Difference (Random) 95% CI Subtotals only
03 Femoral neck Weighted Mean Difference (Random) 95% CI Subtotals only
04 Total hip Weighted Mean Difference (Random) 95% CI Subtotals only
Comparison 03. Adverse Events
Outcome titleNo. of
studies
No. of
participants Statistical method Effect size
01 Total withdrawls Relative Risk (Random) 95% CI Subtotals only
02 Withdrawals due to adverse
events
Relative Risk (Random) 95% CI Subtotals only
03 Number of emergent adverse
events
Relative Risk (Random) 95% CI Subtotals only
04 Serious adverse events Relative Risk (Random) 95% CI Subtotals only
05 Diarrhea Relative Risk (Random) 95% CI Subtotals only
06 Gastritis Relative Risk (Random) 95% CI Subtotals only
07 Deaths Relative Risk (Random) 95% CI Subtotals only
C O V E R S H E E T
Title Strontium ranelate for preventing and treating postmenopausal osteoporosis
Authors O’Donnell S, Cranney A, Wells GA, Adachi JD, Reginster JY
Contribution of author(s) Siobhan O’Donnell prepared the protocol and review for submission.
19Strontium ranelate for preventing and treating postmenopausal osteoporosis (Review)
Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
INTERNAL U
SE ONLY
Ann Cranney conceptualized the idea and supervised all stages of the review.
George Wells provided statistical support.
Jonathan Adachi provided feedback on drafts.
Jean-Yves Reginster facilitated the attainment of unpublished data and provided feedback
on drafts.
All co-reviewers reviewed and approved the final review.
Issue protocol first published 2005/2
Review first published 2006/3
Date of most recent amendment 24 May 2006
Date of most recent
SUBSTANTIVE amendment
24 May 2006
What’s New Information not supplied by author
Date new studies sought but
none found
Information not supplied by author
Date new studies found but not
yet included/excluded
Information not supplied by author
Date new studies found and
included/excluded
Information not supplied by author
Date authors’ conclusions
section amended
Information not supplied by author
Contact address Ms Siobhan O’Donnell
Research Coordinator
Clinical Epidemiology Program
Ottawa Health Research Institute
1053 Carling Avenue, C-414
Ottawa
ON
K1Y 4E9
CANADA
E-mail: [email protected]
Tel: 613-798-5555
Fax: 613-761-5492
DOI 10.1002/14651858.CD005326.pub2
Cochrane Library number CD005326
Editorial group Cochrane Musculoskeletal Group
Editorial group code HM-MUSKEL
20Strontium ranelate for preventing and treating postmenopausal osteoporosis (Review)
Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
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G R A P H S A N D O T H E R T A B L E S
Analysis 01.01. Comparison 01 Fractures, Outcome 01 Verterbral fractures
Review: Strontium ranelate for preventing and treating postmenopausal osteoporosis
Comparison: 01 Fractures
Outcome: 01 Verterbral fractures
Study Strontium Placebo Relative Risk (Random) Weight Relative Risk (Random)
n/N n/N 95% CI (%) 95% CI
01 2 g/day - 1 Year
Meunier 2002 22/85 28/87 22.2 0.80 [ 0.50, 1.29 ]
Meunier 2004-1 44/719 85/723 37.6 0.52 [ 0.37, 0.74 ]
Reginster 2005 51/1817 93/1823 40.2 0.55 [ 0.39, 0.77 ]
Subtotal (95% CI) 2621 2633 100.0 0.59 [ 0.46, 0.74 ]
Total events: 117 (Strontium), 206 (Placebo)
Test for heterogeneity chi-square=2.34 df=2 p=0.31 I =14.4%
Test for overall effect z=4.47 p<0.00001
02 2 g/day - 3 Years
Meunier 2004-1 139/719 222/723 43.8 0.63 [ 0.52, 0.76 ]
Reginster 2005 202/1817 321/1823 56.2 0.63 [ 0.54, 0.74 ]
Subtotal (95% CI) 2536 2546 100.0 0.63 [ 0.56, 0.71 ]
Total events: 341 (Strontium), 543 (Placebo)
Test for heterogeneity chi-square=0.00 df=1 p=0.98 I =0.0%
Test for overall effect z=7.37 p<0.00001
0.1 0.2 0.5 1 2 5 10
Favours strontium Favours placebo
Analysis 01.02. Comparison 01 Fractures, Outcome 02 Non-vertebral fractures
Review: Strontium ranelate for preventing and treating postmenopausal osteoporosis
Comparison: 01 Fractures
Outcome: 02 Non-vertebral fractures
Study Strontium ranelate Placebo Relative Risk (Random) Weight Relative Risk (Random)
n/N n/N 95% CI (%) 95% CI
01 2 g/day - 3 Years
Meunier 2004-1 112/826 122/814 32.6 0.90 [ 0.71, 1.15 ]
Reginster 2005 233/2479 276/2453 67.4 0.84 [ 0.71, 0.99 ]
Subtotal (95% CI) 3305 3267 100.0 0.86 [ 0.75, 0.98 ]
Total events: 345 (Strontium ranelate), 398 (Placebo)
Test for heterogeneity chi-square=0.29 df=1 p=0.59 I =0.0%
Test for overall effect z=2.22 p=0.03
0.1 0.2 0.5 1 2 5 10
Favours strontium Favours placebo
21Strontium ranelate for preventing and treating postmenopausal osteoporosis (Review)
Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
INTERNAL U
SE ONLY
Analysis 02.01. Comparison 02 BMD, Outcome 01 Lumbar spine BMD not adjusted for strontium content
Review: Strontium ranelate for preventing and treating postmenopausal osteoporosis
Comparison: 02 BMD
Outcome: 01 Lumbar spine BMD not adjusted for strontium content
Study Strontium Ranelate Placebo Weighted Mean Difference (Random) Weight Weighted Mean Difference (Random)
N Mean(SD) N Mean(SD) 95% CI (%) 95% CI
01 0.5 g/day - 2 Years
Meunier 2002 80 5.87 (6.59) 87 1.25 (5.30) 47.5 4.62 [ 2.80, 6.44 ]
Reginster 2002-1 35 1.90 (3.59) 30 -0.75 (3.02) 52.5 2.65 [ 1.04, 4.26 ]
Subtotal (95% CI) 115 117 100.0 3.59 [ 1.66, 5.51 ]
Test for heterogeneity chi-square=2.52 df=1 p=0.11 I =60.4%
Test for overall effect z=3.65 p=0.0003
02 1 g/d - 2 Years
Meunier 2002 86 8.33 (8.65) 87 1.25 (5.30) 50.3 7.08 [ 4.94, 9.22 ]
Reginster 2002-1 29 5.53 (5.12) 30 -0.75 (3.02) 49.7 6.28 [ 4.13, 8.43 ]
Subtotal (95% CI) 115 117 100.0 6.68 [ 5.16, 8.20 ]
Test for heterogeneity chi-square=0.27 df=1 p=0.61 I =0.0%
Test for overall effect z=8.63 p<0.00001
03 2 g/day - 2 Years
Meunier 2002 85 13.61 (8.87) 87 1.25 (5.30) 20.8 12.36 [ 10.17, 14.55 ]
Meunier 2004-1 719 9.99 (9.83) 723 -1.02 (6.10) 79.2 11.01 [ 10.17, 11.85 ]
Subtotal (95% CI) 804 810 100.0 11.29 [ 10.22, 12.37 ]
Test for heterogeneity chi-square=1.27 df=1 p=0.26 I =21.3%
Test for overall effect z=20.59 p<0.00001
-100.0 -50.0 0 50.0 100.0
Favours placebo Favours strontium
22Strontium ranelate for preventing and treating postmenopausal osteoporosis (Review)
Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
INTERNAL U
SE ONLY
Analysis 02.02. Comparison 02 BMD, Outcome 02 Lumbar spine adjusted for strontium content
Review: Strontium ranelate for preventing and treating postmenopausal osteoporosis
Comparison: 02 BMD
Outcome: 02 Lumbar spine adjusted for strontium content
Study Strontium Ranelate Placebo Weighted Mean Difference (Random) Weight Weighted Mean Difference (Random)
N Mean(SD) N Mean(SD) 95% CI (%) 95% CI
01 0.5 g/day - 2 Years
Meunier 2002 80 3.11 (5.92) 87 1.23 (5.31) 48.2 1.88 [ 0.17, 3.59 ]
Reginster 2002-1 35 -0.78 (3.42) 30 -0.98 (3.14) 51.8 0.20 [ -1.40, 1.80 ]
Subtotal (95% CI) 115 117 100.0 1.01 [ -0.63, 2.66 ]
Test for heterogeneity chi-square=1.98 df=1 p=0.16 I =49.5%
Test for overall effect z=1.20 p=0.2
02 1 g/day - 2 Years
Meunier 2002 86 3.20 (7.16) 87 1.23 (5.31) 58.7 1.97 [ 0.09, 3.85 ]
Reginster 2002-1 29 1.41 (5.33) 30 -0.98 (3.14) 41.3 2.39 [ 0.15, 4.63 ]
Subtotal (95% CI) 115 117 100.0 2.14 [ 0.70, 3.58 ]
Test for heterogeneity chi-square=0.08 df=1 p=0.78 I =0.0%
Test for overall effect z=2.92 p=0.004
03 2 g/day - 2 Years
Meunier 2002 85 5.45 (6.80) 87 1.23 (5.31) 41.9 4.22 [ 2.39, 6.05 ]
Meunier 2004-1 719 5.13 (8.56) 723 -1.18 (6.26) 58.1 6.31 [ 5.54, 7.08 ]
Subtotal (95% CI) 804 810 100.0 5.44 [ 3.41, 7.46 ]
Test for heterogeneity chi-square=4.26 df=1 p=0.04 I =76.6%
Test for overall effect z=5.27 p<0.00001
-10.0 -5.0 0 5.0 10.0
Favours placebo Favours strontium
23Strontium ranelate for preventing and treating postmenopausal osteoporosis (Review)
Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
INTERNAL U
SE ONLY
Analysis 02.03. Comparison 02 BMD, Outcome 03 Femoral neck
Review: Strontium ranelate for preventing and treating postmenopausal osteoporosis
Comparison: 02 BMD
Outcome: 03 Femoral neck
Study Strontium Ranelate Placebo Weighted Mean Difference (Random) Weight Weighted Mean Difference (Random)
N Mean(SD) N Mean(SD) 95% CI (%) 95% CI
01 0.5 g/day - 2 Years
Meunier 2002 80 0.24 (3.01) 87 -0.47 (9.39) 53.5 0.71 [ -1.37, 2.79 ]
Reginster 2002-1 35 0.46 (4.70) 30 -0.87 (4.46) 46.5 1.33 [ -0.90, 3.56 ]
Subtotal (95% CI) 115 117 100.0 1.00 [ -0.52, 2.52 ]
Test for heterogeneity chi-square=0.16 df=1 p=0.69 I =0.0%
Test for overall effect z=1.29 p=0.2
02 1 g/day - 2 Years
Meunier 2002 86 1.41 (3.45) 87 -0.47 (9.39) 55.3 1.88 [ -0.22, 3.98 ]
Reginster 2002-1 30 2.45 (4.78) 30 -0.87 (4.46) 44.7 3.32 [ 0.98, 5.66 ]
Subtotal (95% CI) 116 117 100.0 2.52 [ 0.96, 4.09 ]
Test for heterogeneity chi-square=0.80 df=1 p=0.37 I =0.0%
Test for overall effect z=3.16 p=0.002
03 2 g/day - 2 Years
Meunier 2002 85 5.36 (8.22) 87 -0.47 (9.39) 4.9 5.83 [ 3.19, 8.47 ]
Meunier 2004-1 719 3.55 (6.47) 723 -2.18 (5.06) 95.1 5.73 [ 5.13, 6.33 ]
Subtotal (95% CI) 804 810 100.0 5.73 [ 5.15, 6.32 ]
Test for heterogeneity chi-square=0.01 df=1 p=0.94 I =0.0%
Test for overall effect z=19.22 p<0.00001
04 2 g/day - 3 Years
Meunier 2004-1 719 5.51 (7.58) 723 -2.79 (5.67) 35.7 8.30 [ 7.61, 8.99 ]
Reginster 2005 1393 5.65 (7.90) 1395 -2.57 (5.80) 64.3 8.22 [ 7.71, 8.73 ]
Subtotal (95% CI) 2112 2118 100.0 8.25 [ 7.84, 8.66 ]
Test for heterogeneity chi-square=0.03 df=1 p=0.86 I =0.0%
Test for overall effect z=39.17 p<0.00001
-10.0 -5.0 0 5.0 10.0
Favours placebo Favours strontium
24Strontium ranelate for preventing and treating postmenopausal osteoporosis (Review)
Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
INTERNAL U
SE ONLY
Analysis 02.04. Comparison 02 BMD, Outcome 04 Total hip
Review: Strontium ranelate for preventing and treating postmenopausal osteoporosis
Comparison: 02 BMD
Outcome: 04 Total hip
Study Strontium ranelate Placebo Weighted Mean Difference (Random) Weight Weighted Mean Difference (Random)
N Mean(SD) N Mean(SD) 95% CI (%) 95% CI
01 2 g/day - 3 Years
Meunier 2004-1 719 7.33 (7.67) 723 -2.49 (5.84) 38.8 9.82 [ 9.12, 10.52 ]
Reginster 2005 1393 7.09 (8.71) 1395 -2.74 (6.19) 61.2 9.83 [ 9.27, 10.39 ]
Subtotal (95% CI) 2112 2118 100.0 9.83 [ 9.39, 10.26 ]
Test for heterogeneity chi-square=0.00 df=1 p=0.98 I =0.0%
Test for overall effect z=43.90 p<0.00001
-100.0 -50.0 0 50.0 100.0
Favours placebo Favours strontium
Analysis 03.01. Comparison 03 Adverse Events, Outcome 01 Total withdrawls
Review: Strontium ranelate for preventing and treating postmenopausal osteoporosis
Comparison: 03 Adverse Events
Outcome: 01 Total withdrawls
Study Strontium ranelate Placebo Relative Risk (Random) Weight Relative Risk (Random)
n/N n/N 95% CI (%) 95% CI
01 0.5 g/d
Meunier 2002 20/85 17/91 59.6 1.26 [ 0.71, 2.24 ]
Reginster 2002-1 5/40 10/40 40.4 0.50 [ 0.19, 1.33 ]
Subtotal (95% CI) 125 131 100.0 0.87 [ 0.36, 2.11 ]
Total events: 25 (Strontium ranelate), 27 (Placebo)
Test for heterogeneity chi-square=2.55 df=1 p=0.11 I =60.7%
Test for overall effect z=0.31 p=0.8
02 2 g/d
Meunier 2002 20/87 17/91 1.5 1.23 [ 0.69, 2.19 ]
Meunier 2004-1 198/826 182/814 16.0 1.07 [ 0.90, 1.28 ]
Reginster 2005 839/2526 870/2503 82.5 0.96 [ 0.88, 1.03 ]
Subtotal (95% CI) 3439 3408 100.0 0.98 [ 0.91, 1.05 ]
Total events: 1057 (Strontium ranelate), 1069 (Placebo)
Test for heterogeneity chi-square=2.01 df=2 p=0.37 I =0.3%
Test for overall effect z=0.65 p=0.5
0.1 0.2 0.5 1 2 5 10
Favours strontium Favours placebo
25Strontium ranelate for preventing and treating postmenopausal osteoporosis (Review)
Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
INTERNAL U
SE ONLY
Analysis 03.02. Comparison 03 Adverse Events, Outcome 02 Withdrawals due to adverse events
Review: Strontium ranelate for preventing and treating postmenopausal osteoporosis
Comparison: 03 Adverse Events
Outcome: 02 Withdrawals due to adverse events
Study Strontium ranelate Placebo Relative Risk (Random) Weight Relative Risk (Random)
n/N n/N 95% CI (%) 95% CI
01 0.5 g/d
Meunier 2002 15/85 14/91 76.1 1.15 [ 0.59, 2.23 ]
Reginster 2002-1 4/40 6/40 23.9 0.67 [ 0.20, 2.18 ]
Subtotal (95% CI) 125 131 100.0 1.01 [ 0.56, 1.80 ]
Total events: 19 (Strontium ranelate), 20 (Placebo)
Test for heterogeneity chi-square=0.61 df=1 p=0.43 I =0.0%
Test for overall effect z=0.02 p=1
02 2 g/d
Meunier 2002 11/87 14/91 8.3 0.82 [ 0.39, 1.71 ]
Meunier 2004-1 140/826 95/814 36.4 1.45 [ 1.14, 1.85 ]
Reginster 2005 611/2526 541/2503 55.4 1.12 [ 1.01, 1.24 ]
Subtotal (95% CI) 3439 3408 100.0 1.20 [ 0.96, 1.50 ]
Total events: 762 (Strontium ranelate), 650 (Placebo)
Test for heterogeneity chi-square=4.65 df=2 p=0.10 I =57.0%
Test for overall effect z=1.58 p=0.1
0.1 0.2 0.5 1 2 5 10
Favours strontium Favours placebo
26Strontium ranelate for preventing and treating postmenopausal osteoporosis (Review)
Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
INTERNAL U
SE ONLY
Analysis 03.03. Comparison 03 Adverse Events, Outcome 03 Number of emergent adverse events
Review: Strontium ranelate for preventing and treating postmenopausal osteoporosis
Comparison: 03 Adverse Events
Outcome: 03 Number of emergent adverse events
Study Strontium ranelate Placebo Relative Risk (Random) Weight Relative Risk (Random)
n/N n/N 95% CI (%) 95% CI
01 0.5 g/d
Meunier 2002 70/85 83/91 42.7 0.90 [ 0.80, 1.02 ]
Reginster 2002-1 37/40 39/40 57.3 0.95 [ 0.86, 1.05 ]
Subtotal (95% CI) 125 131 100.0 0.93 [ 0.86, 1.00 ]
Total events: 107 (Strontium ranelate), 122 (Placebo)
Test for heterogeneity chi-square=0.48 df=1 p=0.49 I =0.0%
Test for overall effect z=1.89 p=0.06
02 2 g/d
Meunier 2002 78/87 83/91 3.2 0.98 [ 0.89, 1.08 ]
Meunier 2004-1 730/826 711/814 22.9 1.01 [ 0.98, 1.05 ]
Reginster 2005 2220/2526 2225/2503 73.9 0.99 [ 0.97, 1.01 ]
Subtotal (95% CI) 3439 3408 100.0 0.99 [ 0.98, 1.01 ]
Total events: 3028 (Strontium ranelate), 3019 (Placebo)
Test for heterogeneity chi-square=1.26 df=2 p=0.53 I =0.0%
Test for overall effect z=0.72 p=0.5
0.1 0.2 0.5 1 2 5 10
Favours strontium Favours placebo
27Strontium ranelate for preventing and treating postmenopausal osteoporosis (Review)
Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
INTERNAL U
SE ONLY
Analysis 03.04. Comparison 03 Adverse Events, Outcome 04 Serious adverse events
Review: Strontium ranelate for preventing and treating postmenopausal osteoporosis
Comparison: 03 Adverse Events
Outcome: 04 Serious adverse events
Study Strontium ranelate Placebo Relative Risk (Random) Weight Relative Risk (Random)
n/N n/N 95% CI (%) 95% CI
01 0.5 g/d
Meunier 2002 11/80 17/87 76.1 0.70 [ 0.35, 1.41 ]
Reginster 2002-1 5/40 4/40 23.9 1.25 [ 0.36, 4.32 ]
Subtotal (95% CI) 120 127 100.0 0.81 [ 0.44, 1.48 ]
Total events: 16 (Strontium ranelate), 21 (Placebo)
Test for heterogeneity chi-square=0.63 df=1 p=0.43 I =0.0%
Test for overall effect z=0.69 p=0.5
02 2 g/d
Meunier 2002 16/85 17/87 1.9 0.96 [ 0.52, 1.78 ]
Meunier 2004-1 188/826 188/814 22.5 0.99 [ 0.83, 1.18 ]
Reginster 2005 624/2526 611/2503 75.6 1.01 [ 0.92, 1.11 ]
Subtotal (95% CI) 3437 3404 100.0 1.01 [ 0.92, 1.09 ]
Total events: 828 (Strontium ranelate), 816 (Placebo)
Test for heterogeneity chi-square=0.08 df=2 p=0.96 I =0.0%
Test for overall effect z=0.12 p=0.9
0.1 0.2 0.5 1 2 5 10
Favours strontium Favours placebo
Analysis 03.05. Comparison 03 Adverse Events, Outcome 05 Diarrhea
Review: Strontium ranelate for preventing and treating postmenopausal osteoporosis
Comparison: 03 Adverse Events
Outcome: 05 Diarrhea
Study Strontium ranelate Placebo Relative Risk (Random) Weight Relative Risk (Random)
n/N n/N 95% CI (%) 95% CI
01 2 g/d
Meunier 2002 3/87 6/91 4.9 0.52 [ 0.13, 2.03 ]
Meunier 2004-1 50/826 29/814 31.6 1.70 [ 1.09, 2.66 ]
Reginster 2005 169/2526 125/2503 63.5 1.34 [ 1.07, 1.68 ]
Subtotal (95% CI) 3439 3408 100.0 1.38 [ 1.02, 1.87 ]
Total events: 222 (Strontium ranelate), 160 (Placebo)
Test for heterogeneity chi-square=2.87 df=2 p=0.24 I =30.3%
Test for overall effect z=2.06 p=0.04
0.1 0.2 0.5 1 2 5 10
Favours strontium Favours placebo
28Strontium ranelate for preventing and treating postmenopausal osteoporosis (Review)
Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
INTERNAL U
SE ONLY
Analysis 03.06. Comparison 03 Adverse Events, Outcome 06 Gastritis
Review: Strontium ranelate for preventing and treating postmenopausal osteoporosis
Comparison: 03 Adverse Events
Outcome: 06 Gastritis
Study Strontium ranelate Placebo Relative Risk (Random) Weight Relative Risk (Random)
n/N n/N 95% CI (%) 95% CI
01 2 g/d
Meunier 2002 5/87 2/91 5.0 2.61 [ 0.52, 13.12 ]
Meunier 2004-1 30/826 45/814 40.7 0.66 [ 0.42, 1.03 ]
Reginster 2005 58/2526 68/2503 54.3 0.85 [ 0.60, 1.19 ]
Subtotal (95% CI) 3439 3408 100.0 0.81 [ 0.56, 1.17 ]
Total events: 93 (Strontium ranelate), 115 (Placebo)
Test for heterogeneity chi-square=2.90 df=2 p=0.23 I =31.0%
Test for overall effect z=1.13 p=0.3
0.01 0.1 1 10 100
Favours strontium Favours placebo
Analysis 03.07. Comparison 03 Adverse Events, Outcome 07 Deaths
Review: Strontium ranelate for preventing and treating postmenopausal osteoporosis
Comparison: 03 Adverse Events
Outcome: 07 Deaths
Study Strontium ranelate Placebo Relative Risk (Random) Weight Relative Risk (Random)
n/N n/N 95% CI (%) 95% CI
01 0.5 g/d
Meunier 2002 4/85 3/91 100.0 1.43 [ 0.33, 6.19 ]
x Reginster 2002-1 0/40 0/40 0.0 Not estimable
Subtotal (95% CI) 125 131 100.0 1.43 [ 0.33, 6.19 ]
Total events: 4 (Strontium ranelate), 3 (Placebo)
Test for heterogeneity: not applicable
Test for overall effect z=0.48 p=0.6
02 2 g/d
Meunier 2002 0/87 3/91 2.2 0.15 [ 0.01, 2.85 ]
Meunier 2004-1 29/826 21/814 34.3 1.36 [ 0.78, 2.37 ]
Reginster 2005 142/2526 159/2503 63.5 0.88 [ 0.71, 1.10 ]
Subtotal (95% CI) 3439 3408 100.0 0.99 [ 0.64, 1.53 ]
Total events: 171 (Strontium ranelate), 183 (Placebo)
Test for heterogeneity chi-square=3.50 df=2 p=0.17 I =42.8%
Test for overall effect z=0.06 p=1
0.001 0.01 0.1 1 10 100 1000
Favours strontium Favours placebo
29Strontium ranelate for preventing and treating postmenopausal osteoporosis (Review)
Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
INTERNAL U
SE ONLY